U.S. patent number 5,561,142 [Application Number 08/445,630] was granted by the patent office on 1996-10-01 for substituted sulfonamides as selective .beta..sub.3 agonists for the treatment of diabetes and obesity.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Michael H. Fisher, Elizabeth M. Naylor, Dong Ok, Hyun Ok, Thomas Shih, Ann E. Weber.
United States Patent |
5,561,142 |
Fisher , et al. |
October 1, 1996 |
Substituted sulfonamides as selective .beta..sub.3 agonists for the
treatment of diabetes and obesity
Abstract
Substituted sulfonamides are selective .beta..sub.3 adrenergic
receptor agonists with very little .beta..sub.1 and .beta..sub.2
adrenergic receptor activity and as such the compounds are capable
of increasing lipolysis and energy expenditure in cells. The
compounds thus have potent activity in the treatment of Type II
diabetes and obesity. The compounds can also be used to lower
triglyceride levels and cholesterol levels or raise high density
lipoprotein levels or to decrease gut motility. In addition, the
compounds can be used to reduced neurogenic inflammation or as
antidepressant agents. The compounds are prepared by coupling an
aminoalkylphenyl-sulfonamide with an appropriately substituted
epoxide. Compositions and methods for the use of the compounds in
the treatment of diabetes and obesity and for lowering triglyceride
levels and cholesterol levels or raising high density lipoprotein
levels or for increasing gut motility are also disclosed.
Inventors: |
Fisher; Michael H. (Ringoes,
NJ), Naylor; Elizabeth M. (Scotch Plains, NJ), Ok;
Dong (Edison, NJ), Weber; Ann E. (Scotch Plains, NJ),
Shih; Thomas (Edison, NJ), Ok; Hyun (Edison, NJ) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
26926674 |
Appl.
No.: |
08/445,630 |
Filed: |
May 22, 1995 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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404565 |
Mar 21, 1995 |
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233166 |
Apr 26, 1994 |
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Current U.S.
Class: |
514/312; 514/318;
514/337; 514/338; 514/340; 514/342; 546/153; 546/194; 546/268.4;
546/268.7; 546/269.1; 546/269.7; 546/270.7; 546/271.4; 546/272.1;
546/272.4; 546/272.7; 546/274.4; 546/275.4; 546/276.1; 546/277.4;
546/278.1; 546/281.7; 546/283.4; 546/286; 546/338 |
Current CPC
Class: |
C07C
311/21 (20130101); C07C 311/47 (20130101); C07D
209/08 (20130101); C07D 213/38 (20130101); C07D
213/73 (20130101); C07D 215/36 (20130101); C07D
233/32 (20130101); C07D 271/06 (20130101); C07D
401/12 (20130101); C07D 405/12 (20130101); C07D
413/12 (20130101); C07D 417/12 (20130101); C07D
417/14 (20130101); C07D 471/04 (20130101) |
Current International
Class: |
C07C
311/21 (20060101); C07C 311/00 (20060101); C07C
311/47 (20060101); C07D 233/00 (20060101); C07D
233/32 (20060101); C07D 405/00 (20060101); C07D
209/08 (20060101); C07D 209/00 (20060101); C07D
213/38 (20060101); C07D 405/12 (20060101); C07D
213/73 (20060101); C07D 213/00 (20060101); C07D
413/12 (20060101); C07D 215/36 (20060101); C07D
413/00 (20060101); C07D 215/00 (20060101); C07D
417/00 (20060101); C07D 271/00 (20060101); C07D
471/00 (20060101); C07D 417/12 (20060101); C07D
271/06 (20060101); C07D 417/14 (20060101); C07D
401/12 (20060101); C07D 401/00 (20060101); C07D
471/04 (20060101); C07D 413/12 (); C07D 213/30 ();
A61K 031/44 (); A61K 031/47 () |
Field of
Search: |
;546/153,194,269,271,275,276,277,280,338
;514/312,318,337,338,340,342 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0091749 |
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Oct 1983 |
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EP |
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0007206 |
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Jan 1989 |
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EP |
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0427480 |
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May 1991 |
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EP |
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0455006 |
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Nov 1991 |
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EP |
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0516350 |
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Dec 1992 |
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EP |
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0516349 |
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Dec 1992 |
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EP |
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0068669 |
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Jan 1993 |
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EP |
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0565317 |
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Oct 1993 |
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EP |
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0611003 |
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Aug 1994 |
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EP |
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1108577 |
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Apr 1968 |
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GB |
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1565080 |
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Apr 1990 |
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GB |
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WO93/10074 |
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May 1993 |
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WO |
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WO93/22277 |
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Nov 1993 |
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WO |
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WO94/02493 |
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Feb 1994 |
|
WO |
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WO94/29290 |
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Dec 1994 |
|
WO |
|
Other References
A A. Larsen, et al, Journal of Medicinal Chemistry, vol. 10, (3)
pp. 462-472, 1967..
|
Primary Examiner: Davis; Zinna Northington
Attorney, Agent or Firm: Yang; Mollie M. Rose; David L.
Parent Case Text
CROSS-REFERENCE
This is a continuation-in-part of co-pending application U.S.
patent application Ser. No. 08/404,565 filed Mar. 21, 1995, now
abandoned, which is a continuation-in-part of U.S. patent
application Ser. No. 08/233,166 filed Apr. 26, 1994, now abandoned
these applications are hereby incorporated by reference in their
entirety.
Claims
What is claimed is:
1. A compound having the formula I: ##STR68## where n is 0 to
5;
m is 0 or 1;
r is 0 to 3;
A is Pyridinyl;
R.sup.1 is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5)
NR.sup.8 R.sup.8, (6) SR.sup.8, (7) trifluoromethyl, (8) C.sub.1
-C.sub.10 alkyl, (9) OR.sup.8, (10) SO.sub.2 R.sup.9, (11)
OCOR.sup.9, (12) NR.sup.8 COR.sup.9, (13) COR.sup.9, (14) NR.sup.8
SO.sub.2 R.sup.9, (15) NR.sup.8 CO.sub.2 R.sup.8, or (16) C.sub.1
-C.sub.10 alkyl substituted by hydroxy, halogen, cyano, NR.sup.8
R.sup.8, SR.sup.8, trifluoromethyl, OR.sup.8, C.sub.3 -C.sub.8
cycloalkyl, phenyl, NR.sup.8 COR.sup.9, COR.sup.9, SO.sub.2
R.sup.9, OCOR.sup.9, NR.sup.8 SO.sub.2 R.sup.9 or NR.sup.8 CO.sub.2
R.sup.8 ;
R.sup.2 and R.sup.3 are independently (1) hydrogen, (2) C.sub.1
-C.sub.10 alkyl or (3) C.sub.1 -C.sub.10 alkyl with 1 to 4
substituents selected from hydroxy, C.sub.1 -C.sub.10 alkoxy, and
halogen;
X is (1) --CH.sub.2 --, (2) --CH.sub.2 --CH.sub.2 --, (3) --CH=CH--
or (4) --CH.sub.2 O--;
R.sup.4 and R.sup.5 are independently (1)hydrogen, (2) C.sub.1
-C.sub.10 alkyl, (3) halogen, (4) NHR.sup.8, (5) OR.sup.8, (6)
SO.sub.2 R.sup.9 or (7) NHSO.sub.2 R.sup.9 ;
R.sup.6 is (1) hydrogen or (2) C.sub.1 -C.sub.10 alkyl;
R.sup.7 is Z-(R.sup.1a).sub.n ;
R.sup.1a is (1) R.sup.1, (2) C.sub.3 -C.sub.8 cycloalkyl, (3)
phenyl optionally substituted with up to 4 groups independently
selected from R.sup.8, NR.sup.8 R.sup.8, OR.sup.8, SR.sup.8 and
halogen, or (4) 5 or 6-membered heterocycle with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen, optionally
substituted with up to four groups independently selected from oxo,
R.sup.8, NR.sup.8 R.sup.8, OR.sup.8, SR.sup.8, and halogen;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, (4) a benzene ring fused to a C.sub.3 -C.sub.8 cycloalkyl
ring, (5) a benzene ring fused to a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, (6) a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5
or 6-membered heterocyclic ring with from 1 to 4 heteroatoms
selected from oxygen, sulfur and nitrogen, or (7) a 5 or 6-membered
heterocyclic ring with from 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen fused to a C.sub.3 -C.sub.8 cycloalkyl
ring;
R.sup.8 is (1 ) hydrogen, (2) C.sub.1 -C.sub.10 alkyl, (3) C.sub.3
-C.sub.8 cycloalkyl, (4) Z optionally having 1 to 4 substituents
selected from halogen, nitro, oxo, NR.sup.10 R.sup.10, C.sub.1
-C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10
alkylthio, and C.sub.1 -C.sub.10 alkyl having 1 to 4 substituents
selected from hydroxy, halogen, CO.sub.2 H, CO.sub.2 --C.sub.1
--C.sub.10 alkyl,
SO.sub.2 --C.sub.1 --C.sub.10 alkyl, C.sub.3 -C.sub.8 cycloalkyl,
C.sub.1 -C.sub.10 alkoxy, and Z optionally substituted by from 1 to
3 of halogen, C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 alkoxy,
or (5) C.sub.1 -C.sub.10 alkyl having 1 to 4 substituents selected
from hydroxy, halogen, CO.sub.2 H, CO.sub.2 --C.sub.1 --C.sub.10
alkyl, SO.sub.2 --C.sub.1 --C.sub.10 alkyl, C.sub.3 -C.sub.8
cycloalkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10 alkyl, and
Z optionally substituted by from 1 to 4 of halogen, C.sub.1
-C.sub.10 alkyl or C.sub.1 -C.sub.10 alkoxy;
R.sup.9 is (1) R.sup.8 or (2) NR.sup.8 R.sup.8 ;
R.sup.10 is (1) C.sub.1 -C.sub.10 alkyl, or (2) two R.sup.10 groups
together with the N to which they are attached formed a 5 or
6-membered ring optionally substituted with C.sub.1 -C.sub.10
alkyl; or
a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 where
n is 0 to 3;
m is 1;
r is 0 to 2;
X is --CH.sub.2 --;
R.sup.1 is (1) hydroxy, (2) halogen, (3) cyano, (4)
trifluoromethyl, (5) NR.sup.8 R.sup.8, (6) NR.sup.8 SO.sub.2
R.sup.9, (7) NR.sup.8 COR.sup.9, (8) NR.sup.8 CO.sub.2 R.sup.8, or
(9) C.sub.1 -C.sub.10 alkyl optionally substituted by hydroxy;
R.sup.2, R.sup.3 are independently (1) hydrogen or (2) methyl;
R.sup.4, R.sup.5 and R.sup.6 are each hydrogen;
R.sup.7 is Z-(R.sup.1a).sub.n.
3. A compound of claim 1 having the formula Ia: ##STR69## wherein n
is 0 to 3;
m is 1
R.sup.1 is (1) halogen or (2) NR.sup.8 R.sup.8 ; R.sup.2, R.sup.3
are independently hydrogen or methyl;
R.sup.1a is (1) halogen, (2) C.sub.1 -C.sub.10 alkyl, (3) NR.sup.8
R.sup.8, (4) NR.sup.8 COR.sup.9, (5) NR.sup.8 CO.sub.2 R.sup.8, (6)
COR.sup.9, (7) OCOR.sup.9, or (8) a 5 or 6-membered heterocycle
with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, optionally substituted with up to four groups
independently selected from oxo, halogen, R.sup.8, NR.sup.8
R.sup.8, OR.sup.8, and SR.sup.8 ;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, (4) benzene ring fused to a 5 or 6-membered heterocyclic
ring with from 1 to 3 heteroatoms selected from oxygen, sulfur and
nitrogen, or (5) a 5 or 6-membered heterocyclic ring with from 1 to
4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a
C.sub.3 -C.sub.8 cycloalkyl ring;
X is --CH.sub.2 --.
4. A compound of claim 3 wherein R.sup.2 and R.sup.3 are each
hydrogen.
5. A compound of claim 1 having the formula Id ##STR70## n is 0 or
1; R.sup.1 is NR.sup.8 R.sup.8 ;
R.sup.2 and R.sup.3 are independently (1) hydrogen, or (2)
methyl;
B is (1 ) hydrogen, (2) benzene fused to the benzene ting to form
naphthyl, or (3) a 5 or 6-membered heterocycle with 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen atom fused to
the benzene ring;
R.sup.1a is (1) halogen, (2) C.sub.1 -C.sub.10 alkyl, (3) NR.sup.8
R.sup.8, (4) NR.sup.8 COR.sup.9, (5) NR.sup.8 CO.sub.2 R.sup.8, (6)
COR.sup.9, or (7) a 5 or 6-membered heterocycle with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen, optionally
substituted with up to four groups independently selected from oxo,
R.sup.8, SR.sup.8, OR.sup.8, and NR.sup.8 R.sup.8 ; when B and the
benzene ring form a fused ting system, R.sup.1a is attached to
either ring;
R.sup.8 is (1) hydrogen, (2) C.sub.1 -C.sub.10 alkyl, (3) Z
optionally having 1 to 4 substituents selected from nitro, oxo, and
NR.sup.10 R.sup.10, or (5) C.sub.1 -C.sub.10 alkyl having 1 to 4
substituents selected from hydroxy, halogen, C.sub.1 -C.sub.10
alkyl, C.sub.3 -C.sub.8 cycloalkyl, and Z optionally substituted by
from 1 to 4 of halogen, C.sub.1 -C.sub.10 alkyl or C.sub.1
-C.sub.10 alkoxy;
R.sup.9 is (1) R.sup.8 or (2) NR.sup.8 R.sup.8 ;
R.sup.10 is (1) C.sub.1 -C.sub.10 alkyl, or (2) two R.sup.10 groups
together with the N to which they are attached formed a 5 or
6-membered ting optionally substituted with C.sub.1 -C.sub.10
alkyl; and
Z is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with from
1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a
benzene ring fused to a 5 or 6-membered heterocyclic ring with from
1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(4) a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen fused to a
C.sub.3 -C.sub.8 cycloalkyl ring.
6. A compound of claim 1 having the formula Ie ##STR71## n is 0 or
1; R.sup.1a is (1) halogen, (2) NR.sup.8 COR.sup.9, or (3) a
5-membered heterocycle substituted with 0 or 1 oxo selected from
imidazolidinone, imidazolone, oxadiazole, oxazole, triazole and
tetrazolone, optionally substituted with up to three groups
independently selected from R.sup.8 ;
R.sup.8 is (1) hydrogen, (2) C.sub.1 -C.sub.10 alkyl, or (3)
C.sub.1 -C.sub.10 alkyl having 1 to 4 substituents selected from
hydroxy, halogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8
cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen,
C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 alkoxy;
R.sup.9 is NR.sup.8 R.sup.8 ; Z is phenyl.
7. A compound of claim 1 selected from the group consisting of:
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(hex
ylaminocarbonylamino)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-iodo
benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-benzen
esulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-2-naph
thalenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-3-quin
olinesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-5-benz
isoxazolesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(he
xylmethylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(di
methylaminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(3
-hexyl-2-imidazolidinon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(hexylaminoc
arbonylamino)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-isopropylben
zenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-2-naphthalenes
ulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-3-quinolinesul
fonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(hexylmethy
laminocarbonyl)amino]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-i
midazolidinon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-iodobenzenes
ulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclop
entylpropyl)-2-imidazolidinon-1-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2-i
midazolidinon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-i
midazolon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2-i
midazolon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclop
entylpropyl)-2-imidazolon-1-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-octylthia
zol-2-yl )-5-indolinesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyl-[1
,2,4]-oxadiazol-3-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyl-[1,
2,4]-oxadiazol-3-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyl-[1
,2,4]-oxadiazol-3-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyl-[1,
2,4]-oxadiazol-3-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclop
entylethyl)-[1,2,4]-oxadiazol-3-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclop
entylpropyl)-[1,2,4]ooxadiazol-3-yl]benzensulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentyloxa
zol-5-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexyloxaz
ol-5-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyloxa
zol-5-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyloxaz
ol-5-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclop
entylethyl)oxazol-5-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclop
entylpropyl)oxazol-5-yl]benzenesulfonamide;
N-[4-[2-[[2-h
ydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyl-5-tetrazolon-1-
yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyl-5-t
etrazolon-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclop
entylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(cyclopen
tylmethyl)oxazol-5-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-diphenylh
ydroxymethyl-5-methyl-[1,2,3]-triazol-2-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[bis(4-fl
uorophenyl)hydroxymethyl]-5-methyl-[1,2,3]-triazol-2-yl]benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexylpyra
zol-1-yl)benzenesulfonamide;
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(1-hydrox
ypentyl)-[1,2,4]-oxadiazol-3-yl]benzenesulfonamide; and
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[(4-fluor
ophenyl)hydroxymethyl]-5-methyl-[1,2,3]-triazol-2-yl]benzenesulfonamide.
8. A compound of claim 1 with the structural formula Ic:
##STR72##
9. A compound of claim 1 which is
(R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-
cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide or a
pharmaceutically acceptable salt thereof.
10. The dihydrochoride salt of the compound of claim 9.
11. A method for the treatment of diabetes which comprises
administering to a diabetic patient an effective amount of a
compound of claim 1.
12. A method for the treatment of obesity which comprises
administering to an obese patient an effective amount of a compound
of claim 1.
13. A method for lowering triglyceride levels and cholesterol
levels or raising high density lipoprotein levels which comprises
administering to a patient needing lower triglyceride and
cholesterol levels or higher high density lipoprotein levels an
effective amount of a compound of claim 1.
14. A method for decreasing gut motility which comprises
administering to a patient in need of decreased gut motility, an
effective amount of a compound of claim 1.
15. A method for reducing neurogenic inflammation of airways which
comprises administering to a patient in need of reduced neurogenic
inflammation, an effective amount of a compound of claim 1.
16. A method for reducing depression which comprises administering
to a depressed patient an effective amount of a compound of claim
1.
17. A method for treating gastrointestinal disorders which
comprises administering to a patient with gastrointestinal
disorders an effective amount of a compound of claim 1.
18. A composition for the treatment of diabetes or obesity or for
lowering triglyceride or cholesterol levels or increasing high
density lipoprotein levels or for decreasing gut motility or for
reducing neurogenic inflammation or for treating depression or for
treating gastrointestinal disorders which comprises an inert
carrier and an effective amount of a compound of claim 1.
Description
BACKGROUND OF THE INVENTION
.beta.-Adrenoceptors have been subclassified as .beta..sub.1 and
.beta..sub.2 since 1967. Increased heart rate is the primary
consequence of .beta..sub.1 -receptor stimulation, while
bronchodilation and smooth muscle relaxation typically result from
.beta..sub.2 stimulation. Adipocyte lipolysis was initially thought
to be solely a .beta..sub.1 -mediated process. However, more recent
results indicate that the receptor-mediating lipolysis is atypical
in nature. These atypical receptors, later called .beta..sub.3
-adrenoceptors, are found on the cell surface of both white and
brown adipocytes where their stimulation promotes both lipolysis
(breakdown of fat) and energy expenditure.
Early developments in this area produced compounds with greater
agonist activity for the stimulation of lipolysis (.beta..sub.3
activity) than for stimulation of atrial rate (.beta..sub.1) and
tracheal relaxation (.beta..sub.2). These early developments
disclosed in Ainsworth et al., U.S. Pat. Nos. 4,478,849 and
4,396,627, were derivatives of phenylethanolamines.
Such selectivity for .beta..sub.3 -adrenoceptors could make
compounds of this type potentially useful as antiobesity agents. In
addition, these compounds have been reported to show
antihyperglycemic effects in animal models of non-insulin-dependent
diabetes mellitus.
A major drawback in treatment of chronic diseases with .beta..sub.3
agonists is the potential for stimulation of other .beta.-receptors
and subsequent side effects. The most likely of these include
muscle tremor (.beta..sub.2) and increased heart rate
(.beta..sub.1). Although these phenylethanolamine derivatives do
possess some .beta..sub.3 selectivity, side effects of this type
have been observed in human volunteers. It is reasonable to expect
that these side effects resulted from partial .beta..sub.1 and/or
.beta..sub.2 agonism.
More recent developments in this area are disclosed in Ainsworth et
al., U.S. Pat. No. 5,153,210, Caulkett et al., U.S. Pat. No.
4,999,377, Alig et al., U.S. Pat. No. 5,017,619, Lecount et al.,
European Patent 427480 and Bloom et al., European Patent
455006.
Even though these more recent developments purport to describe
compounds with greater .beta..sub.3 selectivity over the
.beta..sub.1 and .beta..sub.2 activities, this selectivity was
determined using rodents, in particular, rats as the test animal.
Because even the most highly selective compounds, as determined by
these assays, still show signs of side effects due to residual
.beta..sub.1 and .beta..sub.2 agonist activity when the compounds
are tested in humans, it has become apparent that the rodent is not
a good model for predicting human .beta..sub.3 selectivity.
Recently, assays have been developed which more accurately predict
the effects that can be expected in humans. These assays utilize
cloned human .beta..sub.3 receptors which have been expressed in
Chinese hamster ovary cells. See Emorine et al, Science, 1989,
245:1118-1121; and Liggett, Mol. Pharmacol., 1992, 42:634-637. The
agonist and antagonist effects of the various compounds on the
cultivated cells provide an indication of the antiobesity and
antidiabetic effects of the compounds in humans.
SUMMARY OF THE INVENTION
The instant invention is concerned with substituted sulfonamides
which are useful as antiobesity and antidiabetic compounds. Thus,
it is an object of this invention to describe such compounds. It is
a further object to describe the specific preferred stereoisomers
of the substituted sulfonamides. A still further object is to
describe processes for the preparation of such compounds. Another
object is to describe methods and compositions which use the
compounds as the active ingredient thereof.
Further objects will become apparent from reading the following
description .
DESCRIPTION OF THE INVENTION
The present invention provides compounds having the formula I:
##STR1## where n is
m is 0to 5;
0or 1;
r is 0to 3;
A is (1) a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen, 2) a benzene
ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen, 3) a 5 or
6-membered heterocyclic ring with from 1 to 4 heteroatoms selected
from oxygen, sulfur and nitrogen fused to a 5 or 6-membered
heterocyclic ring with from 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen, (4) phenyl, or (5) a benzene ring
fused to a C.sub.3 -C.sub.8 cycloalkyl ring;
R.sup.1 is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5)
NR.sup.8 R.sup.8, (6) SRS, (7) trifluoromethyl, (8) C.sub.1
-C.sub.10 alkyl, (9) ORS, (10) SO.sub.2 R.sup.9, (11) OCOR.sup.9,
(12) NR.sup.8 COR.sup.9, (13) COR.sup.9, (14) NR.sup.8 SO.sub.2
R.sup.9, (15) NR.sup.8 CO.sub.2 R.sup.8, or (16) C.sub.1 -C.sub.10
alkyl substituted by hydroxy, halogen, cyano, NR.sup.8 R.sup.8,
SR.sup.8, trifluoromethyl, OR.sup.8, C.sub.3 -C.sub.8 cycloalkyl,
phenyl, NR.sup.8 COR.sup.9, COR.sup.9, SO.sub.2 R.sup.9,
OCOR.sup.9, NR.sup.8 SO.sub.2 R.sup.9 or NR.sup.8 CO.sub.2 R.sup.8
;
R.sup.2 and R.sup.3 are independently (1) hydrogen, (2) C.sub.1
-C.sub.10 alkyl or (3) C.sub.1 -C.sub.10 alkyl with 1 to 4
substituents selected from hydroxy, C.sub.1 -C.sub.10 alkoxy, and
halogen;
X is (1) --CH.sub.2 --, (2) --CH.sub.2 --CH.sub.2 --, (3) --CH=CH--
or (4) --CH.sub.2 O--;
R.sup.4 and R.sup.5 are independently (1)hydrogen, (2) C.sub.1
-C.sub.10 alkyl, (3) halogen, (4) NHR.sup.8, (5) OR.sup.8, (6)
SO.sub.2 R.sup.9 or (7) NHSO.sub.2 R.sup.9 ;
R6 is (1) hydrogen or (2) C.sub.1 -C.sub.10 alkyl;
R.sup.7 is Z-(R.sup.1a).sub.n ;
R.sup.1a is (1) R.sup.1, with the proviso that when A is phenyl,
R.sup.1a is not C.sub.1 -C.sub.10 alkyl, (2) C.sub.3 -C.sub.8
cycloalkyl, 3) phenyl optionally substituted with up to 4 groups
independently selected from R.sup.8, NR.sup.8 R.sup.8, OR.sup.8,
SR.sup.8 and halogen, or (4) 5 or 6-membered heterocycle with from
1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,
optionally substituted with up to four groups independently
selected from oxo, R.sup.8, NR.sup.8 R.sup.8, OR.sup.8, SR.sup.8,
and halogen;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, (4) a benzene ring fused to a C.sub.3 -C.sub.8 cycloalkyl
ring, (5) a benzene ring fused to a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, (6) a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen fused to a 5
or 6-membered heterocyclic ring with from 1 to 4 heteroatoms
selected from oxygen, sulfur and nitrogen, or (7) a 5 or 6-membered
heterocyclic ring with from 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen fused to a C.sub.3 -C.sub.8 cycloalkyl
ring;
R.sup.8 is (1) hydrogen, (2) C.sub.1 -C.sub.10 alkyl, (3) C.sub.3
-C.sub.8 cycloalkyl, (4) Z optionally having 1 to 4 substituents
selected from halogen, nitro, oxo, NR.sup.10 R.sup.10, C.sub.1
-C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, C.sub.1 -C.sub.10
alkylthio, and C.sub.1 "C.sub.10 alkyl having 1 to 4 substituents
selected from hydroxy, halogen, CO.sub.2 H, CO.sub.2 -C.sub.1
-C.sub.10 alkyl, SO.sub.2 -C.sub.1 -C.sub.10 alkyl, C.sub.3
-C.sub.8 cycloalkyl, C.sub.1 -C.sub.10 alkoxy, and Z optionally
substituted by from 1 to 3 of halogen, C.sub.1 -C.sub.10 alkyl or
C.sub.1 -C.sub.10 alkoxy, or (5) C.sub.1 -C.sub.10 alkyl having 1
to 4 substituents selected from hydroxy, halogen, CO.sub.2 H,
CO.sub.2 --C.sub.1 --C.sub.10 alkyl, SO.sub.2 --C.sub.1 --C.sub.10
alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.10 alkoxy,
C.sub.1 -C.sub.10 alkyl, and Z optionally substituted by from 1 to
4 of halogen, C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10
alkoxy;
R.sup.9 is (1) R.sup.8 or (2) NR.sup.8 R.sup.8 ;
R.sup.10 is (1) C.sub.1 -C.sub.10 alkyl, or (2) two R.sup.10 groups
together with the N to which they are attached formed a 5 or
6-membered ring optionally substituted with C.sub.1 -C.sub.10
alkyl; or
a pharmaceutically acceptable salt thereof.
In one embodiment of the instant invention A is a 5 or 6-membered
heterocyclic ring with from 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen, a benzene ring fused to a 5 or
6-membered heterocyclic ring with from 1 to 4 heteroatoms selected
from oxygen, sulfur and nitrogen, or a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1
to 4 heteroatoms selected from oxygen, sulfur and nitrogen.
In another embodiment of the instant invention A is phenyl or
benzene fused to a C.sub.3 -C.sub.8 cycloalkyl ring.
Preferred compounds of the instant invention are realized when in
the above structural formula I:
R.sup.2 and R.sup.3 are hydrogen or methyl;
X is --CH.sub.2 --;
n is 0 to 3;
m is 1;
r is 0 to 2; and
R.sup.4, R.sup.5 and R.sup.6 are hydrogen.
Other preferred compounds of the instant invention are realized
when in the above structural formula I:
A is phenyl or a 6-membered heterocyclic ring with 1 or 2
heteroatoms selected from nitrogen and sulfur;
R.sup.1 is hydroxy, halogen, cyano, trifluoromethyl, NR.sup.8
R.sup.8, NR.sup.8 SO.sub.2 R.sup.9, NR.sup.8 COR.sup.9, NRSCO.sub.2
R.sup.8, C.sub.1 -C.sub.6 alkyl optionally substituted by hydroxy;
and
r is 0 or 2.
More preferred compounds are represented by the formula Ia:
##STR2## wherein n is 0to 3;
m is 1
R.sup.1 is (1) halogen or (2) NR.sup.8 R.sup.8 ;
R.sup.2, R.sup.3 are independently hydrogen or methyl;
R.sup.1a is (1) halogen, (2) C.sub.1 -C.sub.10 alkyl, (3) NR.sup.8
R.sup.8, (4) NR.sup.8 COR.sup.9, (5) NR.sup.8 CO.sub.2 R.sup.8, (6)
COR.sup.9, (7) OCOR.sup.9, or (8) a 5 or 6-membered heterocycle
with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, optionally substituted with up to four groups
independently selected from oxo, halogen, R.sup.8, NR.sup.8
R.sup.8, OR.sup.8, and SR.sup.8 ;
Z is (1) phenyl, (2) naphthyl, (3) a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, (4) benzene ring fused to a 5 or 6-membered heterocyclic
ring with from 1 to 3 heteroatoms selected from oxygen, sulfur and
nitrogen, or (5) a 5 or 6-membered heterocyclic ring with from 1 to
4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a
C.sub.3 -C.sub.8 cycloalkyl ting;
X is --CH.sub.2 --; and
R.sup.8 and R.sup.9 are as defined in claim 1.
Even more preferred compounds are those represented by formula Id:
##STR3## n is 0 or 1; R.sup.1 is NR.sup.8 R.sup.8 ;
R.sup.2 and R.sup.3 are independently (1) hydrogen, or (2)
methyl;
B is (1) hydrogen, (2) benzene fused to the benzene ring to form
naphthyl, or (3) a 5 or 6-membered heterocycle with 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen atom fused to
the benzene ring;
R.sup.1a is (1) halogen, (2) C.sub.1 -C.sub.10 alkyl, (3) NR.sup.8
R.sup.8, (4) NR.sup.8 COR.sup.9, (5) NR.sup.8 CO.sub.2 R.sup.8, (6)
COR.sup.9, or (7) a 5 or 6-membered heterocycle with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen, optionally
substituted with up to four groups independently selected from oxo,
R.sup.8, SR.sup.8, OR.sup.8, and NR.sup.8 R.sup.8 ; when B and the
benzene ring form a fused ring system, R.sup.1a is attached to
either ring;
R.sup.8 is (1) hydrogen, (2) C.sub.1 -C.sub.10 alkyl, (3) Z
optionally having 1 to 4 substituents selected from nitro, oxo, and
NR.sup.10 R.sup.10, or (5) C.sub.1 -C.sub.10 alkyl having 1 to 4
substituents selected from hydroxy, halogen, C.sub.1 -C.sub.10
alkyl, C.sub.3 -C.sub.8 cycloalkyl, and Z optionally substituted by
from 1 to 4 of halogen, C.sub.1 -C.sub.10 alkyl or C.sub.1
-C.sub.10 alkoxy;
R.sup.9 is (1) R.sup.8 or (2) NR.sup.8 R.sup.8 ;
R.sup.10 is (1) C.sub.1 -C.sub.10 alkyl, or
(2) two R.sup.10 groups together with the N to which they are
attached formed a 5 or 6-membered ring optionally substituted with
C.sub.1 -C.sub.10 alkyl; and
Z is (1) phenyl, (2) a 5 or 6-membered heterocyclic ring with from
1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, (3) a
benzene ring fused to a 5 or 6-membered heterocyclic ring with from
1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, or
(4) a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen fused to a
C.sub.3 -C.sub.8 cycloalkyl ring. Most preferred compounds are
those having the formula Ie ##STR4## n is 0or 1; R.sup.1a is (1)
halogen, (2) NR.sup.8 COR.sup.9, or (3) a 5-membered heterocycle
substituted with 0 or 1 oxo selected from imidazolidinone,
imidazolone, oxadiazole, oxazole, triazole and tetrazolone,
optionally substituted with up to three groups independently
selected from R.sup.8 ;
R.sup.8 is (1) hydrogen, (2) C.sub.1 -C.sub.10 alkyl, or (3)
C.sub.1 -C.sub.10 alkyl having 1 to 4 substituents selected from
hydroxy, halogen, C.sub.1 -C.sub.10 alkyl, C.sub.3 -C.sub.8
cycloalkyl, and Z optionally substituted by from 1 to 4 of halogen,
C.sub.1 -C.sub.10 alkyl or C.sub.1 -C.sub.10 alkoxy;
R.sup.9 is NR.sup.8 R.sup.8 ;
Z is phenyl.
Other more preferred compounds are represented by formula Ib:
##STR5## wherein n is
0to 3;
m is
R.sup.1a is (1) hydroxy, (2) cyano, (3) NR.sup.8 R.sup.8 or (4)
halogen;
R.sup.1a is (1) halogen, (2) NR.sup.8 R.sup.8, (3) NR.sup.8
COR.sup.9, (4) NR.sup.8 CO.sub.2 R.sup.8, (5) OCOR.sup.9, or (6) a
5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected
from oxygen, sulfur and nitrogen, optionally substituted with up to
three groups independently selected from oxo, halogen, R.sup.8,
NR.sup.8 R.sup.8, OR.sup.8 and SR.sup.8 ;
Z is (1) phenyl, (2) naphthyl or (3) benzene ring fused to a 5 or
6-membered heterocyclic ring with from 1 to 4 heteroatoms selected
from oxygen, sulfur and nitrogen;
X is --CH.sub.2 --; and
R.sup.2 and R.sup.3 are independently hydrogen or methyl.
Representative antiobesity and antidiabetic compounds of the
present invention include the following:
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(hex
ylaminocarbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-iodo
benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-benzen
esulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyllamino]ethyl]phenyl]-2-naph
thalenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-3-quin
olinesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyllphenyl]-5-ben
zisoxazolesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyllamino]ethyl]phenyl]-4-[(he
xylmethylaminocarbonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[(di
methylaminocarbonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(3-h
exyl-2-imidazolidon- 1-yl)benzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]-phenyl]-4-(h
exylaminocarbonylamino)benzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]-phenyl]-4-io
dobenzenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]-phenyl]benze
nesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]-phenyl]-2-na
phthalenesulfonamide
N-[4-[3-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]propyl]-phenyl]-3-qu
inolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(hexylaminoc
arbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-isopropylben
zenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-2-naphthalenes
ulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-3-quinolinesul
fonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino
]ethyl]phenyl]-4-[(hexylmethylaminocarbonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-i
midazolidinon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-iodobenzenes
ulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclop
entylpropyl)-[1,2,4]-oxadiazol-3-yl]benzensulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(1-oxohepty
l)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(1-oxo-4-ph
enylbutyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(propoxycar
bonyl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(fur-2-yl
methyl)amino]carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(2-phenyl
ethyl)amino]carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[[(2-indol-
3-ylethyl)amino]carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[(octylamin
o)carbonyl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-
1-[(hexylamino)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[(octylamino
)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-
1-[(N-methyl-N-octylamino)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(1-oxononyl)
-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-
1-(4-methylthiazo-1-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-
1-(4-octylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-ethyl-5-m
ethylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl
)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2imidazolidinon-1-yl)benzenesulfonam
ide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(4,4,4-tr
ifluorobutyl)-2-imidazolidinon-1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-phenyl
propyl)-2-imidazolidinon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(4,4,5,5,
5-pentafluoropentyl)-2-imidazolidinon-1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-cycloh
exylethyl)-2-imidazolidinon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-[3-(4-chl
orophenyl)propyl]-2-imidazolidinon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-pentyl-2-
imidazolidinon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl
)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclopentylpropyl)-2-imidazolidinon-
1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[cyclopentyl
ethyl)-2-imidazolidinon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cycloh
exylpropyl)-2-imidazolidinon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2,2-dime
thylhexyl)-2-imidazolidinon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2-i
midazolon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(4,4,4-tr
ifluorobutyl)-2-imidazolon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-2-i
midazolon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclop
entylpropyl)-2-imidazolon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyl-3-o
xo-[1,2,4]-triazol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyl-5-t
etrazolon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyl-5-t
etrazolon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclop
entylpropyl)-5-tetrazolon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentyloxa
zol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyloxaz
ol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclop
entylethyl)oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(4-ethyl-5-
methylthiazol-2-yl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[(4,5,6,7-te
trahydrobenzothiazol-2-yl)amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexylimid
azol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(1-methyl-2-
octylimidazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[1-methyl-2-
(2-cyclopentylethyl)imidazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[1-methyl-2-
[2-(4-fluorophenyl)ethyl]imidazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyl-[1
,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclop
entylethyl)-[1,2,4]-oxadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyl-[1
,2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyl-[1,
2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexylthio
-[1,2,4]-triazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(4-propy
lpiperidin-1-yl)-1,1-dioxo-[1,2,5]-thiadiazol-3-yl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(hexylme
thylamino)-1,1-dioxo-[1,2,5]-thiadiazol-3-yl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[[4-(heptylm
ethylamino)-1,1-dioxo-[1,2,5]-thiadiazol-3-yl]amino]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(1-octyl-2,4
-imidazolidinedion-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-nitrop
henyl)-5-pyrazolon- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(1-hydrox
y-1-hexylheptyl)-5-methyl-[1,2,3]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(1-hydrox
yheptyl)-5-methyl-[1,2,3 ]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-methylpropyl]-phenyl]-4-(
3-hexyl-2-imidazolidinon- 1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-methylpropyl]-phenyl]-4-i
odobenzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]-2-methylpropyl]-phenyl]-4-[
[(hexylamino)carbonyl]amino]benzenesulfonamide
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-4-iodobenzene-sulfona
mide
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-2-naphthalene-sulfona
mide
N-[4-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]phenyl]-3-quinoline-sulfonami
de
N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-3-isopropyl
benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-2-naphthale
nesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-chlorophenyl)ethyl]amino]ethyl]phenyl]-3-quinoline
sulfonamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl
]-4-(hexylaminocarbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl
]-1-[(octylamino)carbonyl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl
]-4-(3-hexyl-2-imidazolidinon-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]ethyl]-phenyl
]-4-(3-octyl-2-imidazolidinon- 1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-benzenesul
fonamide
N-[4-[2-[[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-4-iodobenz
enesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4-(hexylamin
ocarbonylamino)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3-quinolines
ulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyl-[1,
2,4]-oxadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptyl-5-
methyl-[1,2,3]-tfiazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-2,4
-imidazolidinedion- 1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-(2,4-imidazo
lidinedion-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclop
entylpropyl)-2,4-imidazolidinedion- 1-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl][1,2,4]-oxadiaz
ol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-[1,
2,4]-oxadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-(3-heptyl-[1
,2,4]-oxadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-[1,
2,4]-oxadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-cyclop
entylethyl)-[1,2,4]-oxadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclop
entylpropyl)-[1,2,4]-oxadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-pentyl-[1
,2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexyl-[1,
2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-heptyl-[1
,2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-octyl-[1,
2,4]-thiadiazol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[3-(2-cyclop
entylethyl)-[1,2,4]-thiadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyfidinyl)ethyl]amino]ethyl]phenyl]-4-[3-(3-cyclop
entylpropyl)-[1,2,4]-thiadiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyl-[1
,2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyl-[1,
2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyl-[1
,2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyl-[1,
2,4]-thiadiazol-3-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclop
entylethyl)-[1,2,4 ]-thiadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclop
entylpropyl)-[1,2,4]-thiadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-pentyl-3-
oxo-[1,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyl-3-o
xo-[1,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptyl-3-
oxo-[1,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyl-3-o
xo-[1,2,4]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2-cyclop
entylethyl)-3-oxo-[1,2,4]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclop
entylpropyl)-3-oxo-[1,2,4]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyloxa
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyloxaz
ol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyloxa
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyloxaz
ol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclop
entylethyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclop
entylpropyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-pentyloxa
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexyloxaz
ol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptyloxa
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octyloxaz
ol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2-cyclop
entylethyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclop
entylpropyl)oxazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexyloxaz
ol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyloxa
zol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclop
entylpropyl)oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(4-cycloh
exylbutyl)oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-[2-(4-flu
orophenyl)ethyl]oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentyloxa
zol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexyloxaz
ol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyloxa
zol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyloxaz
ol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclop
entylethyl)oxazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclop
entylpropyl)oxazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentylthi
azol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexylthia
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptylthi
azol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octylthia
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclop
entylethyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclop
entylpropyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-pentylthi
azol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-hexylthia
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-heptylthi
azol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-octylthia
zol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(2-cyclop
entylethyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclop
entylpropyl)thiazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentylthi
azol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexylthia
zol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptylthi
azol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2octylthiaz
ol-4-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclop
entylethyl)thiazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclop
entylpropyl)thiazol-4-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentylthi
azol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexylthia
zol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptylthi
azol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octylthia
zol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclop
entylethyl)thiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclop
entylpropyl)thiazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-
1-(5-methylthiazol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-pentylthi
azol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-hexylthia
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-heptylthi
azol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-octylthia
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(2-cyclop
entylethyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(3-cyclop
entylpropyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-pentylthi
azol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-hexylthia
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-heptylthi
azol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[4-(2-cyclop
entylethyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[4-(3-cyclop
entylpropyl)thiazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-methyloxa
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-pentyloxa
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-hexyloxaz
ol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-heptyloxa
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-octyloxaz
ol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(2-cyclop
entylethyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(3-cyclop
entylpropyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-methyloxa
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-pentyloxa
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-hexyloxaz
ol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-heptyloxa
zol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(4-octyloxaz
ol-2-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[4-(2-cyclop
entylethyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[4-(3-cyclop
entylpropyl)oxazol-2-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(3-methyl-[1
,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(3-pentyl-[1
,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(3-hexyl-[1,
2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(3-heptyl-[1
,2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(3-octyl-[1,
2,4]-oxadiazol-5-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[3-(2-cyclop
entylethyl)-[1,2,4]-oxadiazol-5-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[3-(3-cyclop
entylpropyl)-[1,2,4]-oxadiazol-5-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-methyl-[1
,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-pentyl-[1
,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-hexyl-[1,
2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-heptyl-[1
,2,4]-oxadiazol-3-yl)-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-(5-octyl-[1,
2,4]-oxadiazol-5-yl)-3-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(2-cyclop
entylethyl)-[1,2,4]-oxadiazol-3-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-1-[5-(3-cyclop
entylpropyl)-[1,2,4]-oxadiazol-3-yl]-5-indolinesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(cyclopen
tylmethyl)oxazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(4-diphenylh
ydroxymethyl-5-methyl-[1,2,3]-triazol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[bis(4-fl
uorophenyl)hydroxymethyl]-5-methyl-[1,2,3]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(3-hexylpyra
zol-1-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(1-hydrox
ypentyl)-[1,2,4]-oxadiazol-3-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[(4-fluor
ophenyl)hydroxymethyl]-5-methyl-[1,2,3]-triazol-2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-pentyltet
razol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-hexyltetr
azol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-heptyltet
razol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(2-octyltetr
azol-5-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclop
entylethyl)tetrazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[2-(3-cyclop
entylpropyl)tetrazol-5-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-pentyltet
razol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-hexyltetr
azol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-heptyltet
razol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-(5-octyltetr
azol-2-yl)benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(2-cyclop
entylethyl)tetrazolo2-yl]benzenesulfonamide
N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[5-(3-cyclop
entylpropyl)tetrazol-2-yl]benzenesulfonamide.
The compounds of the instant invention all have at least one
asymmetric center as noted by the asterisk in structural Formula I.
Additional asymmetric centers may be present on the molecule
depending upon the nature of the various substituents on the
molecule, in particular, R.sup.2 and R.sup.3. Each such asymmetric
center will produce two optical isomers and it is intended that all
such optical isomers, as separated, pure or partially purified
optical isomers or racemic mixtures thereof, be included within the
ambit of the instant invention. In the case of the asymmetric
center represented by the asterisk in Formula I, it has been found
that the compound in which the hydroxy substituent is above the
plane of the structure, as seen in Formula Ic, is more active and
thus more preferred over the compound in which the hydroxy
substituent is below the plane of the structure.
The following stereospecific structure represents the preferred
stereoisomers of the instant invention: ##STR6## where n, m, r, A,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and X
are as defined above under formula I.
Throughout the instant application, the following terms have the
indicated meanings:
The alkyl groups specified above are intended to include those
alkyl groups of the designated length in either a straight or
branched configuration. Exemplary of such alkyl groups are methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl,
isopentyl, hexyl, isohexyl, and the like.
The alkoxy groups specified above are intended to include those
alkoxy groups of the designated length in either a straight or
branched configuration. Exemplary of such alkoxy groups are
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary
butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
The term "halogen" is intended to include the halogen atoms
fluorine, chlorine, bromine and iodine.
Examples of 5 and 6-membered heterocycles and fused heterocycles of
A, Z and R.sup.1a include pyridyl, quinolinyl, pyrimidinyl,
pyrrolyl, thienyl, imidazolyl, thiazolyl, benzimidazolyl,
thiadiazolyl, benzothiadiazolyl, indolyl, indolinyl, benzodioxolyl,
benzodioxanyl, benzothiophenyl, benzofuranyl, benzoxazinyl,
benzisoxazolyl, benzothiazolyl, tetrahydronaphthyl,
dihydrobenzofuranyl, tetrahydroquinolinyl, furopyridine and
thienopyridine.
The preferred values of A and Z are phenyl, naphthyl, benzene ring
fused to a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen, or
heterocycles with from 1 to 4 heteroatoms independently selected
from one of oxygen or sulfur, and/or 1 to 4 nitrogen atoms.
The more preferred values of A are phenyl, pyridyl, quinolinyl,
pyrimidinyl, pyrrolyl, thienyl, imidazolyl, and thiazolyl.
The more preferred values of Z are phenyl, naphthyl, quinolinyl,
thienyl, benzimidazolyl, thiadiazolyl, benzothiadiazolyl, indolyl,
indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl,
benzofuranyl, benzoxazinyl, benzisoxazolyl, benzothiazolyl,
tetrahydronaphthyl, dihydrobenzofuranyl, triazolyl, tetrazolyl,
oxadiazolyl, imidazolyl, oxazolyl, thiazolyl, imidazolidinyl,
pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazolyl,
tetrahydrobenzothiazolyl and tetrahydroquinolinyl. When Z is
attached to --NSO.sub.2 (CH.sub.2).sub.r --, it is preferably
phenyl, naphthyl or a benzene ring fused to a 5 or 6-membered
heterocyclic ring with from 1 to 4 heteroatoms selected from
oxygen, sulfur and nitrogen. When Z is part of the definition of
R8, it is preferably phenyl, a 5 or 6-membered heterocyclic ring
with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, a benzene ring fused to a 5 or 6-membered heterocyclic
ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and
nitrogen, or a 5 or 6-membered heterocyclic ring with from 1 to 4
heteroatoms selected from oxygen, sulfur and nitrogen fused to a
C.sub.3 -C.sub.8 cycloalkyl ring.
The preferred heterocycles of R.sup.1a are thienyl, thiadiazolyl,
triazolyl, tetrazolyl, oxadiazolyl, imidazolyl, oxazolyl,
thiazolyl, imidazolidinyl, isoxazolyl, pyridyl, pyrimidyl, and
pyrazolyl.
Certain of the above defined terms may occur more than once in the
above formula and upon such occurrence each term shall be defined
independently of the other; thus for example, NR.sup.8 R.sup.8 may
represent NH.sub.2, NHCH.sub.3, N(CH.sub.3)CH.sub.2 CH.sub.3, and
the like.
The following abbreviations are used throughout the
specification:
Boc :tert-butyloxycarbonyl
Cbz :carbobenzyloxy
DIP-Cl :diisopinocampheylchloroborane
DMF :dimethylformamide
DMSO :dimethylsulfoxide
HPLC :high pressure liquid chromatography
Me :methyl
MPLC :medium pressure liquid chromatography
Ms :methanesulfonyl (mesyl)
NBS :N-bromosuccinimide
NCS :N-chlorosuccinimide
nHex :n-hexyl
TB AF :tetrabutylammonium fluoride
TBS (TBDMS) :t-butyldimethylsilyl
TFA :trifluoroacetic acid
THF :tetrahydrofuran
The compounds (I) of the present invention can be prepared from
epoxide intermediates such as those of formula II and amine
intermediates such as those of formula III. The preparation of
these intermediates is described in the following schemes. ##STR7##
where n, m, r, A, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7 and X are as defined above.
Compounds II are known in the literature or may be conveniently
prepared by a variety of methods familiar to those skilled in the
art. One common route is illustrated in Scheme 1. Acid chloride 1,
which may be commercially available or readily prepared from the
corresponding acid by treatment with, for example, thionyl chloride
or oxalyl chloride, is treated with diazomethane in a solvent such
as diethyl ether. The resultant diazoketone is then treated with
hydrogen chloride to give chloroketone 2 (X=Cl). The haloketone 2
is then reduced with a reducing agent such as sodium borohydride.
The resultant alcohol 3 is treated with base such as potassium
carbonate in refluxing acetone to provide the desired epoxide II.
The enantiomerically enriched (R) and (S) epoxides II are readily
available by asymmetric reduction of haloketones 2 using chiral
reducing agents such as (-) or (+)-DIP-Cl, (R) or (S)-Alpine borane
or (R) or (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,
3H-pyrrolo[1,2-c][1,3,2]oxazaborole-borane ((R) or
(S)-OAB.multidot.BH.sub.3). ##STR8##
An alternate route to the desired haloketones 2 is illustrated in
Scheme 2. Methylketone 4 may be converted to the corresponding
haloketone using a variety of reagents known to those in the art
and summarized in Larock Comprehensive Organic Transformations;
VCH: New York, 1989, 369-372. Conveniently, methylketone 4 is
treated with chlorine or N-chlorosuccinimide in acetic acid with an
additional acid source such as hydrogen chloride or aluminum
chloride. For the synthesis of 2 (X=Br), bromine, dibromobarbituric
acid or NBS with hydrogen bromide or aluminum bromide may be used.
In some cases, the chloro or bromoketones 2 may be commercially
available. ##STR9##
Many of the methylketones 4 are commercially available or readily
prepared by methods described in the literature and known to those
skilled in the art. R.sup.1 substituents on the acid chlorides 1 or
methylketones 4 may need to be protected during the subsequent
procedures. A description of such protecting groups may be found
in: Protective Groups in Organic Synthesis, 2nd Ed., T. W. Greene
and P. G. M. Wuts, John Wiley and Sons, New York, 1991.
Compounds III can be conveniently prepared by a variety of methods
familiar to those skilled in the art. A convenient route for their
preparation when R.sup.6 is hydrogen is illustrated in Scheme 3.
Compound 5 is selectively protected as a suitable carbamate
derivative 6 with, for example, di-tert-butyl dicarbonate or
carbobenzyloxy chloride. This compound is then treated with a
sulfonyl halide, preferably the sulfonyl chloride 7, and a base
such as pyridine in an anhydrous solvent such as dichloromethane or
chloroform for 0.5 to 24 hours at temperatures of -20.degree. to
50.degree. C., preferably 0.degree. C., to provide the sulfonamide
8. The protecting group is then removed with, for example,
trifluoracetic acid in the case of Boc or catalytic hydrogenation
in the case of Cbz, to give the desired amine 9. ##STR10##
Compounds III where R.sup.6 is not hydrogen may be conveniently
prepared as illustrated in Scheme 4. Sulfonamide 8, prepared as
described above, is alkylated with an appropriate alkylating agent
10 in the presence of base to provide sulfonamide 11. Removal of
the protecting group as above gives the desired compound 9a.
##STR11##
The sulfonyl chlorides 7, many of which are commercially available,
can also be readily prepared by a number of methods familiar to
those skilled in the art. One suitable method involves the addition
of an organolithium reagent or a Grignard reagent to sulfuryl
chloride following the procedure of S. N. Bhattacharya, et. al., J.
Chem. Soc. (C), 1265-1267 (1969). Another convenient method
involves the treatment of a thiol with sulfuryl chloride and a
metal nitrate according to the procedure of Y. J. Park, et. al.,
Chemistry Letters, 1483-1486 (1992). Sulfonic acids are also
conveniently converted to the corresponding sulfonyl chloride by
treatment with PCl.sub.5, PCl.sub.3 or SOCl.sub.2 (J. March,
Advanced Organic Chemistry, 4th Ed., John Wiley and Sons, New York:
1992, p 1297 and references cited therein). Aromatic and
heteroaromatic compounds may be chlorosulfonylated directly by
treatment with Vilsmeier's reagent or chorosulfonic acid (Organic
Synthesis, I, 8).
The diamines 5 are commercially available or readily prepared by
methods described in the literature or known to those skilled in
the art. Compound 5 where R.sup.2 or R.sup.3 is methyl can be
prepared from the corresponding amino acid following the method of
J. D. Bloom, et. al., J. Med. Chem., 35, 3081-3084 (1992). As
illustrated in Scheme 5 for R.sup.3 =methyl, the appropriate (R)
amino acid 12 is esterified, conveniently by treatment with
methanolic hydrochloric acid, and then treated with di-tert-butyl
dicarbonate to give compound 13. The ester group is reduced with a
hydride source such as lithium borohydride and the resultant
alcohol is converted to a leaving group such as a mesylate. Removal
of the Boc protecting groups gives diamine 14. This compound is
subjected to catalytic hydrogenation in the presence of base such
as sodium acetate to give the desired .alpha.-methyl amine 15. The
other enantiomer is available through an analogous sequence
starting with the corresponding (S) amino acid. ##STR12##
Diamines 5 or sulfonamide amines 9 where X is --CH.sub.2 O-- and m
is 1 are also readily prepared by methods described in the
literature or known to those skilled in the art. For example, as
shown in Scheme 6, the sodium salt of 4-nitrophenol 16 is alkylated
with 1-bromo-2-chloroethane, conveninetly in refluxing 2-butanone
with a base such as potassium carbonate to give chloro derivative
17. The chloride is converted to the corresponding amine by
treatment with lithium azide followed by reduction with, for
example, triphenylphosphine in aqueous tetrahydrofuran. Protection
of the resultant amine, conveniently as its t-butyl carbamate by
treatment with di-tertobutyldicarbonate, gives derivative 18. The
nitro group is then reduced, for example, by catalytic
hydrogenation to provide amine 19. Acylation of intermediate 19
with sulfonyl chloride 7, followed by deprotection with acid such
as trifluoroacetic acid gives the desired intermediate 20.
##STR13##
Alternatively, diamine 5 where X is --CH.sub.2 O-- and m is 1 is
available from intermediate 19 by treatment with trifluoroacetic
acid. This diamine may then be modified as illustrated in Scheme
3.
Diamines 5 and sulfonamide amines 9 where X is --CH.sub.2 CH.sub.2
-- and m is 1 are also readily prepared by methods described in the
literature or known to those skilled in the art. For example, as
shown in Scheme 7, bromo derivative 21 is treated with sodium
cyanide to provide nitrile 22. The nitro group is selectively
reduced by treatment with hydrogen and catalytic palladium to
provide amine 23. Amine 23 is acylated with sulfonyl chloride 7 to
give the corresponding sulfonamide 24. Reduction of compound 24
with cobalt chloride and sodium borohydride provides the desired
amine 25. ##STR14##
Alternatively, diamine 5 where X is --CH.sub.2 CH.sub.2 -- and m is
1 is available from intermediate 23 by reduction of the nitrile
group with, for example, cobalt chloride and sodium borohydride.
This diamine may then be modified as illustrated in Scheme 3.
Intermediates II and III are coupled by heating them neat or as a
solution in a polar solvent such as methanol, acetonitrile,
tetrahydrofuran, dimethylsulfoxide or N-methyl pyrrolidinone for 1
to 24 hours at temperatures of 30.degree. to 150.degree. C. to
provide compounds I as shown in Scheme 8. The reaction is
conveniently conducted in refluxing methanol. Alternatively, a salt
of amine III, such as the trifluoroacetate or hydrochloride salt,
may be used. In these cases, a base such as sodium bicarbonate or
diethylisopropylamine is added to the reaction mixture. The product
is purified from unwanted side products by recrystallization,
trituration, preparative thin layer chromatography, flash
chromatography on silica gel as described by W. C. Still, et. al.,
J. Org. Chem. 43, 2923 (1978), medium pressure liquid
chromatography, or HPLC. Compounds which are purified by HPLC may
be isolated as the corresponding salt. Purification of
intermediates is achieved in the same manner. ##STR15##
In some cases, the coupling product I from the reaction described
in Scheme 8 may be further modified, for example, by the removal of
protecting groups or the manipulation of substituents on, in
particular, R.sup.1 and R.sup.7. These manipulations may include,
but are not limited to, reduction, oxidation, alkylation,
acylation, and hydrolysis reactions which are commonly known to
those skilled in the art.
An alternate method for the synthesis of compound I is illustrated
in Scheme 9. Epoxide II is coupled to amine 5 as described above
for coupling intermediates II and III (Scheme 8) to give aniline
derivative 27. The secondary amine is selectively protected, for
example, as a carbamate by treatment with di-tert-butyldicarbonate
to provide carbamate 29. Alternatively, nitro amine 26 is used in
the coupling reaction to provide 28. Following protection as
described above, the nitro group is reduced, for example, by
catalytic hydrogenation with palladium catalyst or raney nickel, to
provide intermediate 29. In some cases, other group may be reduced
concomitantly. For example, if R.sup.1 is halogen in intermediate
28, it may be converted to hydrogen in intermediate 29. Treatment
with a sulfonyl chloride in the presence of a base such as pyridine
followed by removal of the protecting group with, in the case of a
tert-butylcarbamate, acid such as trifluoroacetic acid or
methanolic hydrogen chloride, provides the sulfonamide I.
##STR16##
In some cases, compound I from the reaction sequence illustrated in
Scheme 9 may be further modified, for example, by the removal of
protecting groups or the manipulation of substituents on, in
particular, R.sup.1 and R.sup.7, as described above. In addition,
manipulation of substituents on any of the intermediates in the
reaction sequence illustrated in Scheme 9 may occur. One such
example is illustrated in Scheme 10. Compound 30, which is prepared
as outlined in Scheme 9 from the corresponding epoxide, is
subjected to reduction using tin(II) chloride to provide compound
31. Other examples of substituents on compound I which may be
reduced to the corresponding amine by methods commonly known to
those skilled in the art include nitro groups, nitriles, and
azides. ##STR17##
The compounds (I) of the present invention can also be prepared
from amine intermediates such as those of formula III and
haloketone intermediates such as those of formula 2, as shown in
Scheme 11. Amine III is alkylated with haloketone derivative 2,
conveniently by treatment of a mixture of III and 2 with base such
as potassium carbonate or triethylamine in a polar solvent such as
acetonitrile, acetone or dimethylformamide. The resultant
aminoketone 32 is reduced with, for example, sodium borohydride in
methanol to give the desired aminoalcohol I. ##STR18##
In some cases, the product I from the reaction described in Scheme
11 may be further modified, for example, by the removal of
protecting groups or the manipulation of substituents on, in
particular, R.sup.1 and R.sup.7. These manipulations may include,
but are not limited to, reduction, oxidation, alkylation,
acylation, and hydrolysis reactions which are commonly known to
those skilled in the art.
An alternate synthesis of key intermediate 29 is shown is Scheme
12. The alcohol of intermediate 3 is protected, for example, as its
t-butyldimethylsilyl ether to give TBS derivative 33. This compound
is then treated with amine 5 and a base such as
diisopropylethylamine in a solvent, typically polar aprotic such as
acetonitrile, at temperatures of 25.degree. to 150.degree. C. for 1
to 72 hours. Typically, an iodide source such as sodium iodide is
added to facilitate the reaction. The protecting group is then
removed, in the case of silyl ether, by treatment of the resultant
amine 34 with a fluoride source such as tetrabutylammonium
fluoride. Protection of the secondary amine as before gives key
intermediate 29. ##STR19##
In some cases, compound I may be synthesized directly from
intermediate 27 without protection of the secondary amine. For
example, when R.sup.2 and R.sup.3 are both methyl, aniline
derivative 27 is treated with sulfonyl chloride 7 and a base such
as pyridine in a solvent such as dichloromethane at a temperature
of -30.degree. to 50.degree. C., typically 0.degree. C., to provide
compound I.
In some cases, the product I from the reaction described in Scheme
13 may be further modified, for example, by the removal of
protecting groups or the manipulation of substituents on, in
particular, R.sup.1 and R.sup.7, as described above. ##STR20##
The compounds (I) of the present invention where R.sup.2 and
R.sup.3 are hydrogen can also be prepared from acid intermediates
of formula 36 and aminoalcohols of formula 37, as shown in Scheme
14. Acid 36 is available from the corresponding ester 35, typically
a methyl or ethyl ester, by treatment with sulfonyl chloride 7 and
a base such as pyridine, followed by hydrolysis of the ester with
aqueous acid or base. Acid 36 is coupled to amine 37, which is
known in the literature or readily prepared by methods known to
those skilled in the art, using a coupling agent such as
benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium
hexafluorophosphate or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide to provide
the amide 38. This is treated with a reducing agent, typically
borane, to provide the desired compound I. ##STR21##
Compounds of the general Formula I may be separated into
diastereoisomeric pairs of enantiomers by, for example, fractional
crystallization from a suitable solvent, for example methanol or
ethyl acetate or a mixture thereof. The pair of enantiomers thus
obtained may be separated into individual stereoisomers by
conventional means, for example by the use of an optically active
acid as a resolving agent.
Alternatively, any enantiomer of a compound of the general Formula
I may be obtained by stereospecific synthesis using optically pure
starting materials of known configuration.
The instant compounds can be isolated in the form of their
pharmaceutically acceptable acid addition salts, such as the salts
derived from using inorganic and organic acids. Examples of such
acids are hydrochloric, nitric, sulfuric, phosphoric, formic,
acetic, trifluoroacetic, propionic, maleic, succinic, malonic and
the like. In addition, certain compounds containing an acidic
function such as a carboxy or tetrazole, can be isolated in the
form of their inorganic salt in which the counterion can be
selected from sodium, potassium, lithium, calcium, magnesium and
the like, as well as from organic bases.
As previously indicated, the compounds of the present invention
have valuable pharmacological properties.
The present invention also provides a compound of the general
Formula I or a pharmaceutically acceptable salt thereof for use as
an active therapeutic substance.
In one aspect, the present invention provides a compound of the
general Formula I or a pharmaceutically acceptable ester thereof:
or a pharmaceutically acceptable salt thereof for use in the
treatment of obesity in human or non-human animals.
The present invention further provides a compound of the general
Formula I, or a pharmaceutically acceptable ester thereof; or
pharmaceutically acceptable salt thereof, for use in the treatment
of hyperglycemia (diabetes) in human or non-human animals.
The disease diabetes mellitus is characterized by metabolic defects
in production and utilization of glucose which result in the
failure to maintain appropriate blood sugar levels. The result of
these defects is elevated blood glucose or hyperglycemia. Research
on the treatment of diabetes has centered on attempts to normalize
fasting and postprandial blood glucose levels. Treatments have
included parenteral administration of exogenous insulin, oral
administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are now recognized. Type I
diabetes, or insulin-dependent diabetes, is the result of an
absolute deficiency of insulin, the hormone which regulates glucose
utilization. Type II diabetes, or insulin-independent diabetes,
often occurs in the face of normal, or even elevated levels of
insulin and appears to be the result of the inability of tissues to
respond appropriately to insulin. Most of the Type II diabetics are
also obese.
In addition the compounds of the present invention lower
triglyceride levels and cholesterol levels and raise high density
lipoprotein levels and are therefore of use in combatting medical
conditions wherein such lowering (and raising) is thought to be
beneficial. Thus they may be used in the treatment of
hyper-triglyceridaemia, hypercholesterolaemia and conditions of low
HDL (high density lipoprotein) levels in addition to the treatment
of atherosclerotic disease such as of coronary, cerebrovascular and
peripheral arteries, cardiovascular disease and related
conditions.
Accordingly, in another aspect the present invention provides a
method of lowering triglyceride and/or cholesterol levels and/or
increasing high density lipoprotein levels which comprises
administering, to a human or a non-human animal in need thereof, a
therapeutically effective amount of a compound of the formula (I)
or pharmaceutically acceptable salt thereof. In a further aspect
the present invention provides a method of treating atherosclerosis
which comprises administering, to an animal in need thereof; a
therapeutically effective amount of a compound of the formula (I)
or pharmaceutically acceptable salt thereof. The compositions are
formulated and administered in the same general manner as detailed
below for treating diabetes and obesity. They may also contain
other active ingredients known for use in the treatment of
atherosclerosis and related conditions, for example fibrates such
as clofibrate, bezafibrate and gemfibrozil; inhibitors of
cholesterol biosynthesis such as HMG-CoA reductase inhibitors for
example lovastatin, simvastatin and pravastatin; inhibitors of
cholesterol absorption for example beta-sitosterol and (acyl
CoA:cholesterol acyltransferase) inhibitors for example melinamide;
anion exchange resins for example cholestyramine, colestipol or a
dialkylaminoalkyl derivatives of a cross-linKed dextran; nicotinyl
alcohol, nicotinic acid or a salt thereof; vitamin E; and
thyromimetics.
The compounds of the instant invention also have the effect of
reducing intestinal motility and thus find utility as aiding in the
treatment of various gastrointestinal disorders such as irritable
bowel syndrome. It has been proposed that the motility of
non-sphincteric smooth muscle contraction is mediated by activity
at .beta..sub.3 adrenoreceptors. The availability of a .beta..sub.3
specific agonist, with little activity at .beta..sub.1 and
.beta..sub.2 receptors will assist in the pharmacologic control of
intestinal motility without concurrent cardiovascular effects. The
instant compounds are administered generally as described below
with dosages similar to those used for the treatment of diabetes
and obesity.
It has also been found unexpectedly that the compounds which act as
agonists at .beta..sub.3 adrenoreceptors may be useful in the
treatment of gastrointestinal disorders, especially peptic
ulcerations, esophagitis, gastritis and duodenitis, (including that
induced by H. pylori), intestinal ulcerations (including
inflammatory bowel disease, ulcerative colitis, Crohn's disease and
proctitis) and gastrointestinal ulcerations.
In addition, .beta..sub.3 receptors have been indicated to have an
effect on the inhibition of the release of neuropeptides in certain
sensory fibers in the lung. As sensory nerves may play an important
role in the neurogenic inflammation of airways, including cough,
the instant specific .beta..sub.3 agonists may be useful in the
treatment of neurogenetic inflammation, such as asthma, with
minimal effects on the cardio-pulmonary system.
.beta..sub.3 adrenoreceptors are also able to produce selective
antidepressant effects by stimulating the .beta..sub.3 receptors in
the brain and thus an additional contemplated utility of the
compounds of this invention are as antidepressant agents.
The active compounds of the present invention may be orally
administered as a pharmaceutical composition, for example, with an
inert diluent, or with an assimilable edible carder, or they may be
enclosed in hard or soft shell capsules, or they may be compressed
into tablets, or they may be incorporated directly with the food of
the diet. For oral therapeutic administration, which includes
sublingual administration, these active compounds may be
incorporated with excipients and used in the form of tablets,
pills, capsules, ampules, sachets, elixirs, suspensions, syrups,
and the like. Such compositions and preparations should contain at
least 0.1 percent of active compound. The percentage of active
compound in these compositions may, of course, be varied and may
conveniently be between about 2 percent to about 60 percent of the
weight of the unit. The amount of active compound in such
therapeutically useful compositions is such that an effective
dosage will be obtained. The active compounds can also be
administered intranasally as, for example, liquid drops or
spray.
The effective dosage of active ingredient employed may vary
depending on the particular compound employed, the mode of
administration, the condition being treated and the severity of the
condition being treated.
When treating diabetes mellitus and/or hyperglycemia generally
satisfactory results are obtained when the compounds of the present
invention are administered at a daily dosage of from about 0.001
milligram to about 100 milligram per kilogram of animal body
weight, preferably given in a single dose or in divided doses two
to six times a day, or in sustained release form. In the case of a
70 kg adult human, the total daily dose will generally be from
about 0.07 milligrams to about 350 milligrams. This dosage regimen
may be adjusted to provide the optimal therapeutic response.
When treating obesity, in conjunction with diabetes and/or
hyperglycemia, or alone, generally satisfactory results are
obtained when the compounds of the present invention are
administered at a daily dosage of from 0.01 milligram to about 100
milligrams per kilogram of animal body weight, preferably given in
a single dose or in divided doses two to six times a day, or in
sustained release form. In the case of a 70 kg adult human, the
total daily dose will generally be from about 0.7 milligrams to
about 3500 milligrams. This dosage regimen may be adjusted to
provide the optimal therapeutic response.
The tablets, pills, capsules, and the like may also contain a
binder such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid; a lubricant such as
magnesium stearate; and a sweetening agent such as sucrose, lactose
or saccharin. When a dosage unit form is a capsule, it may contain,
in addition to materials of the above type, a liquid carrier such
as a fatty oil.
Various other materials may be present as coatings or to modify the
physical form of the dosage unit. For instance, tablets may be
coated with shellac, sugar or both. A syrup or elixir may contain,
in addition to the active ingredient, sucrose as a sweetening
agent, methyl and propylparabens as preservatives, a dye and a
flavoring such as cherry or orange flavor.
These active compounds may also be administered parenterally.
Solutions or suspensions of these active compounds can be prepared
in water suitably mixed with a surfactant such as
hydroxy-propylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils.
Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
The following examples are provided so that the invention might be
more fully understood. They should not be construed as limiting the
invention in any way.
EXAMPLE 1 ##STR22##
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(tetrazolo[1,5-a]pyrid-6-yl)e
t hylamine
A solution of 1.62 g (10 mmol) of
(R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (See Fisher and Wyvratt,
European Patent Application 0 318 092 A2 for the synthesis of this
compound.) and 4.1 g (30 mmol) of 2-(4-aminophenyl)ethylamine in 30
mL of methanol was heated at reflux for 5h. The reaction mixture
was concentrated and the residue chromatographed on silica gel (2%
methanol/98% methylene chloride) to give 1.69 g (56%) of the title
compound: .sup.1 H NMR (400 MHz, CD.sub.3 OD) .delta. 9.01 (d, 1H,
J=1.3 Hz), 8.02 (d, 1 H, J=9.2 Hz), 7.82 (dd, 1H, J=1.3, 9.2 Hz),
6.94 (d, 2H, J=6.3 Hz), 6.63 (d, 2H, J=6.3 Hz), 4.91 (m, 1H), 2.82
(m, 4H), 2.67 (t, 2 H, J=7.1Hz).
EXAMPLE 2 ##STR23##
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(tetrazolo[1,5-a]pyrid-6-yl)e
t hylcarbamic acid 1,1-dimethylethyl ester
A solution of 1.69 g (56.7 mmol) of the amine from Example 1 and
1.23 g (56.7 mmol) of di-tert-butyl dicarbonate in 10 mL of
tetrahydrofuran (THF) at 0.degree. C. was stirred for 2 h. The
reaction mixture was concentrated and the residue chromatographed
on silica gel (4% methanol/96% methylene chloride) to afford 2.2 g
(97%) of the title compound: .sup.1 H NMR (400 MHz, CD3OD) .delta.5
8.96 (s, 1H), 8.05 (m, 2H), 7.85 (m, 2H), 6.93 (dd, 2H, J=7.7, 8.3
Hz), 6.66 (d, 2H, J=8.3 Hz), 4.99 (m, 1H), 3.49 (m, 4H), 2.70 (t,
2H, J=6.5 Hz), 1.26 (s, 9H).
EXAMPLE 3 ##STR24## 4-(Hexylaminocarbonylamino)benzenesulfonyl
chloride
Hexylamine, 12.15 ml (9.2 mmol), was added dropwise to a solution
of 10 ml (9.2 mmol) of phenyl isocyanate in THF (150 ml) at
0.degree. C., and stirring was continued for 1 h. The solvent was
removed in vacuo, and the resultant hexyl phenyl urea was used
without further purification.
A 6-g (2.7 mmol) portion was added over 20 min to chlorosulfonic
acid at 0.degree. C., followed by heating at 60.degree. C. for 2h.
After cooling, the mixture was added to ice/water (100 ml) and the
aqueous phase extracted with EtOAc (3.times.100 ml). The combined
organic phase was washed with brine (50 ml), dried with MgSO.sub.4,
concentrated, and purified by flash chromatography (silica gel, 75%
hexane/25% ethyl acetate) to give 6 g (70%) of the title compound:
.sup.1 H NMR (CDCl.sub.3) .delta.7.85 (d, 2H, J=9.6 Hz), 7.54 (d,
2H, J=9.6 Hz), 6.79 (br.s, 1H), 4.71(br. s, 1H), 3.23 (t, 2H, J=8
Hz), 1.54-1.44 (m, 2H), 1.33-1.20 (m, 6H), 0.91-0.79 (m, 3H).
EXAMPLE 4 ##STR25##
(R)-N-[4-[2-[N-(1,1-dimethylethoxycarbonyl)-N-[2-hydroxy-2-(tetra-zolo[1,5
-
alpyrid-6-yl)]ethyl]aminolethyl]phenyll-4-(hexylaminocarbon-ylamino)benzene
sulfonamide
To a stirred solution of 0.200 g (0.502 mmol) of the Boc-compound
from Example 2 in 3 mL of methylene chloride was added 80 mg(1.00
mmol) of pyridine followed by 0.16 g (0.75 mmol) of the sulfonyl
chloride from Example 3. After being stirred for 5h, the reaction
mixture was concentrated and the residue chromatographed on silica
gel (10% methanol/90% methylene chloride) to afford 0.303 g (88%)
of the title compound: .sup.1 H NMR (400 Hz, CD3OD) .delta.8.95 (s,
1H), 8.0-8.08 (m, 1H), 7.75-7.87 (m, 1H), 7.40-7.62 (m, 4H), 7.00
(m, 4H), 4.95 (m, 2H), 3.47 (m, 2H), 3.15 (m, 2H), 2.75 (m, 2H),
1.52 (t, 2H, J=6.0 Hz), 1.33 (m, 8H), 1.21 (s, 9H), 0.90 (t, 3H,
J=6.0 Hz).
EXAMPLE 5 ##STR26##
(R)-N-[4-[2-[[2-hydroxy-2-(6-aminopyridin-3-yl)ethyl]amino]ethyl]-phenyl]-
4 ,-(hexylaminocarbonylamino)benzenesulfonamide
A mixture of 0.302 g (0.44 mmol) of the tetrazine from Example 4,
0.20 g (0.88 mol) of tin(II) chloride dihydrate and 0.3 ml of
concentrated aqueous hydrochloric acid in 2 mL of methanol was
heated at reflux for 5 h. The reaction mixture was concentrated and
the residue purified by reverse-phase MPLC (C8, 47%methanol/53 0.1%
trifluoroacetic acid buffer) to give 0.32 g (78%) of the title
compound as its bistrifluoroacetate salt: .sup.1 H NMR (400 MHz,
CD.sub.3 OD) .delta.5 7.96 (dd, 1H, J=2.0, 9.2 Hz), 7.86 (d, 1H,
J=2.0 Hz), 7.59 (d, 2H, J=8.8 Hz), 7.43 (d, 2H, J=8.8 Hz), 7.14 (d,
2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.03 (d, 1H, J=9.2 Hz), 4.92
(m, 1H), 3.23 (m, 2H), 3.15 (m, 2H), 2.93 (m, 2H, 4.0 Hz), 1.49 (t,
2H, J=6.0Hz), 1.32 (m, 8H), 0.91 (t, 3H, J=6.0 Hz); CI MS m/z
555(M+1).
Following the procedures outlined for Examples 1-5, the compounds
listed in Table 1 were prepared.
TABLE 1 ______________________________________ ##STR27## Ex- am-
Selected ple R .sup.1 H NMR (CD.sub.3 OD) Data
______________________________________ 6 Ph, trifluoroacetate salt
7.74(m, 2H), 7.53(m, 1H), 7.45 (m, 2H). 7 2-naphthyl, 7.93(m, 4H),
7.75(d, 1H, J=1.7 trifluoroacetate salt Hz), 7.61(m, 2H) 8
3-quinolinyl, 9.00(d, 1H, J=2.3Hz), 8.06(m, trifluoroacetate salt
2H), 7.94(m, 2H), 7.72(t, 1H, J= 7.2Hz) 9 1,2-benzisoxazol-5-yl,
9.02(s, 1H), 8.30(d, 1H, J=1.3 trifluoroacetate salt Hz), 7.90(m,
1H), 7.77(m, 1H) 10 4-iodophenyl, 7.83(d, 2H, J=8.6Hz), 7.46(d,
trifluoroacetate salt 2H, J=8.6Hz) 11 4-[(N-hexyl, N-methyl-
7.62(d, 2H, J=4.6Hz), 7.48(d, aminocarbonyl)amino]- 2H, J=4.6Hz),
2.99(s, 3H) phenyl, trifluoroacetate salt 12 4-[(N,N-dimethyl-
3.0(s, 6H) aminocarbonyl)amino]- phenyl, trifluoroacetate salt 13
4-(3-hexyl-2- 3.88-3.83(m, 2H), 3.57-3.50(m, imidazolidinon-1- 2H),
2.89-2.95(m, 2H), 1.61-1.52 yl)phenyl, (m, 2H), 1.37-1.30(m, 6H),
and trifluoroacetate salt 0.93-0.88(m, 3H)
______________________________________
EXAMPLE 14 ##STR28## 3-(2-Chloroacetyl)pyridine hydrochloride
To a solution of 12 g (11 mL, 100 mmol) of 3-acetylpyridine in 100
mL of ethyl ether was added 100 mL of 1 M ethereal hydrogen
chloride. The resultant precipitate was filtered and 15.0 g (95.2
mmol) was collected and placed in a 500-mL round bottom flask
equipped with a magnetic stir bar. To this was added 95 mL of 1 M
hydrogen chloride in acetic acid. After the mixture was stirred
until all the solid had dissolved, 12.7 g (95.2 mmol) of
N-chlorosuccinimide (NCS) was added in one portion. The solution
turned yellow and the NCS gradually dissolved. After 4 h, a white
precipitate had formed. The mixture was allowed to stir for 2.5
days. It was then filtered. The solid collected was washed with 10
mL of acetic acid and 200 mL of ethyl ether to give 15.2 g (83%) of
the title compound as a white solid: 1H NMR (200 MHz, d.sub.6
-DMSO) .delta.9.22 (t, H, J=1 Hz), 8.29 (dd, 1H, J=1.6, 5.1 Hz),
8.55 (td, 1H, J=2, 8.1 Hz), 7.82 (ddd, 1H, J=0.8, 5.1, 8.1 Hz),
5.27 (s, 2H).
EXAMPLE 15 ##STR29##
(R)-.alpha.-Chloromethyl-3-pyridinemethanol
To a stirred solution of 3.67 g (11.5 mmol) of
(-)-B-chlorodiisopinocampheylborane [(-)-DIP-C1]in 11 mL of THF at
-25.degree. C. was added a slurry of 1.00 g (5.21 mmol) of the
product from Example 14 in 5 mL of THF via a cannula. Following the
addition of 0.80 mL (5.79 mmol) of triethylamine, the reaction
mixture was stirred at -25.degree. C. for 4 days. To the mixture
was added 10 mL of water which was then allowed to warm to room
temperature. To the mixture was added 20 mL of ethyl acetate and
the organic phase separated. The aqueous phase was neutralized with
saturated NaHCO.sub.3 solution then extracted six times with ethyl
acetate. The combined organic phase was concentrated in vacuo to
afford a yellow oil. Hash chromatography (silica gel, 75-100% ethyl
acetate-hexanes) afforded 561 mg (68%) of the title compound as a
pale yellow oil: .sup.1 H NMR (400 MHz, CD3OD) .delta.5 8.58 (d,
1H, J=1.8 Hz), 8.46 (dd, 1H, J =4.9, 1.5 Hz), 7.90 (d, 1H, J=7.9
Hz), 7.44 (dd, 1H, J=7.9, 4.9 Hz), 4.93 (m, 1H), 3.75 (m, 2H).
EXAMPLE 16 ##STR30## (R)-(Pyrid-3-yl)oxirane
To a solution of 557 mg (3.55 mmol) of the product from Example 15
in 16 mL of acetone was added 1.80 g of potassium carbononate. The
mixture was heated at reflux for 20 h then cooled to room
temperature. The mixture was filtered and the flitrate evaporated
in vacuo. Flash chromatography (silica gel, 2% methanol-methylene
chloride) afforded 262 mg (61%) of the title compound as a pale
yellow oil: 1H NMR (200 MHz, CDCl.sub.3) 8 8.54 (m, 2H), 7.52 (m,
1H), 7.24 (m, 1H), 3.86 (dd, 1H, J=4.0, 2.5 Hz), 3.17 (dd, 1H,
J=5.4, 4.0 Hz), 2.80 (dd, 1H, J=5.4, 2.5 Hz).
EXAMPLE 17 ##STR31##
(R)-N-[2-[4-(Aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylamine
To a stirred solution of 377 mg (2.44 mmol) of
4-aminophenethylamine in 10 mL of methanol was added a solution of
300 mg (2.48 mmol) of the product from Example 16 in 15 mL of
methanol. The mixture was heated at reflux for 16 h then cooled to
room temperature. The methanol was removed in vacuo and the residue
chromatographed (silica gel, 6-8% methanol, 1% ammonia-methylene
chloride) to afford 101 mg (16%) of the title compound together
with 279 mg of a mixture that was rechromatographed (5% methanol,
1% ammonia-methylene chloride) to give a further 54 mg (9%) of the
title compound as an off-white solid: .sup.1 H NMR (500 MHz,
CD.sub.3 OD) .delta.8.52 (d, 1H, J=1.8 Hz), 8.43 (dd, 1H, J=4.8,
1.4 Hz), 7.81 (m, 1H), 7.40 (m, 1H), 6.95 (d, 2H, J=8.3 Hz), 6.67
(d, 2H, J=8.3 Hz), 4.81 (m, 1H), 2.90-2.65 (m, 6H).
EXAMPLE 18 ##STR32##
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylcarbamic
acid 1,1-dimethylethyl ester
A solution of 386 mg(1.77 mmol) of di-tert-butyl dicarbonate in 3.5
mL of THF was added, via a cannula, to a stirred slurry of 456 mg
(1.77 mmol) of the product from Example 17 in 3.6 mL of THF cooled
to 0.degree. C. The yellow solution was stirred at 0.degree. C. for
3 h, then the THF was removed in vacuo. Hash chromatography (silica
gel, 10% methanol, 1% ammonia-methylene chloride) afforded 549 mg
(87%) of the title compound as an off white solid: .sup.1 H NMR
(500 MHz, CD.sub.3 OD, mixture of rotomers) .delta.5 8.45 (m, 2H),
7.83 (d, 0.6H, J=7.4 Hz), 7.78 (d, 0.4H, J=6.9 Hz), 7.41 (m, 1H),
6.94 (d, 0.8H, J=8.0 Hz), 6.89 (d, 1.2H, J=7.8 Hz), 6.66 (d, 2H,
J=7.3 Hz), 4.89 (m, 1H), 3.42-3.21 (m, 4H), 2.67 (m, 2H), 1.39 (s,
5.4H), 1.36 (s, 3.6H).
An alternative synthesis of the aniline derivative in Example 18 is
illustrated in Examples 19-23:
EXAMPLE 19 ##STR33## 2-Chloro-5-(2-bromoacetyl)pyridine
A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 mL of THF
was added via canula to a solution of 1.44 g of dibromobarbituric
acid (DBBA) in 10 mL of THF. The resultant solution was heated at
50.degree.-55.degree. C. for 12 h, and then an additional 0.72 g
DBBA was added. After stirring at 50.degree.-55.degree. C. for 2.5
more hours, 0.36 g DBBA was added. The mixture was allowed to stir
for 2 h at which point NMR analysis of an aliquot indicated 87%
conversion. The reaction mixture was cooled, diluted with ethyl
acetate, washed with two portions of saturated aqueous sodium
bicarbonate, water, and brine, dried over magnesium sulfate and
concentrated. Purification by flash chromatography (silica gel, 15%
ethyl acetate/hexane) provided 0.86 g (73%) of the title compound
as a white solid: .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.8.96
(d, 1H, J=2.6 Hz), 8.21 (dd, 1H, J=2.5, 8.3 Hz), 7.46 (d, 1H, J=8.4
Hz), 4.37 (s, 2H). The NMR also indicated the presence of the
corresponding 2-bromo derivative. The .about.4:1 mixture was
carried on through the synthesis.
EXAMPLE 20 ##STR34##
(R)-.alpha.-Bromomethyl-3-(6-chloropyridine)methanol
To a solution of 602 mg(1.88 mmol) of (-)-DIP-C1 in 0.5 mL of THF
at -25.degree. C. was added via canula 200 mg of ketone from
Example 19 in 1.5 mL of THF at -25.degree. C. The reaction mixture
was allowed to stir at -25.degree. C. for 17 h. It was then
quenched by the addition of water and extracted with ether. The
ether phase was diluted with ethyl acetate, washed with two
portions of saturated aqueous sodium bicarbonate, water, and brine,
dried over magnesium sulfate and concentrated. Purification by
flash chromatography (silica gel, 15 and 25% ethyl acetate/hexane)
gave 170 mg (84%) of the title compound: 1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.38 (d, 1H), 7.70 (dd, 1H), 7.32 (d, 1H), 4.97
(m, 1H), 3.61 (dd, 1H), 3.50 (dd, 2.85 (d,
EXAMPLE 21 ##STR35## (R)-(2-chloropyrid-5-yl)oxirane
To a solution of 100 mg of bromoalcohol from Example 20 in mL of
1:1 THF:water was added 1 mL of 5 N aqueous sodium hydroxide
solution. The mixture was allowed to stir for 10 min. It was then
extracted with three portions of dichloromethane. The combined
organic phases were washed with two portions of water and brine,
dried over magnesium sulfate, and concentrated to give 98 mg (93%)
of the title compound which was used without further purification:
.sup.1 H NMR (400 MHz, CDCl.sub.3) 8 8.34 (d, 1H), 7.48 (dd, 1H),
7.29 (d, 1H), 3.86 (dd, 1H), 3.18 (dd, 1H), 2.78 (dd, 1H).
EXAMPLE 22 ##STR36##
(R)-N-[2-[4-(Nitrophenyl)]ethyl]-2-hydroxy-2-(2-chloropyrid-5-yl)ethylcarb
a mic acid 1,1-dimethylethyl ester
Following the procedure outlined in Examples 17 and 18, the title
compound was prepared from the epoxide from Example 21 and
4-nitrophenylethylamine: .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.
8.32 (d, 1H, J=1.3 Hz), 8.13 (d, 2H, J=8.6 Hz), 7.66 (br m, 1H),
7.30 (d, 2H, J=8.1 Hz), 7.27 (br m, 1H), 4.94 (br m), 3.38 (br m,
4H), 2.84 (br m, 2H), 1.40 (s, 9H).
EXAMPLE 23 ##STR37##
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(pyrid-3-yl)ethylcarbamic
acid 1,1-dimethylethyl ester
To a solution of 80 mg (0.19 mmol) of the nitro compound from
Example 22 in 2 mL of ethanol was added 0.114 mL (0.57 mmol) of 5 N
aqueous sodium hydroxide solution and 20 mg of raney nickel. The
reaction mixture was shaken at room temperature under 45 psi
hydrogen for 16 h. The mixture was neutralized with saturated
aqueous sodium phosphate monobasic and extracted with three
portions of ethyl acetate. The combined organic phases were washed
with water and brine, dried (magnesium sulfate), and concentrated
to give 40 mg (59%) of the title compound which was identical to
the sample prepared in Example 18.
EXAMPLE 24 ##STR38## 4-(3-Hexyl-2-imidazolon-1-yl)benzenesulphonyl
chloride
Hexyl iodide (50 mmol, 7.38 ml) was added to a mixture of 2-amino
acetaldehyde dimethyl acetal (100 mmol, 11 ml) and potassium
carbonate (50 mmol, 6.9 g) in DMF (10 ml) at 0.degree. C. Stirring
was continued for 16h before diluting with ethyl acetate (200 ml),
and ffitering the solution through a plug of celite. Concentration
in vacuo was follwed by column chromatography (eluant ethyl
acetate) to give N-hexyl 2-amino acetaldehyde dimethyl acetal (7.39
g, 78%) as a colourless oil.
To the amine (38.6 mmol, 7.3 g) in methylene chloride (100 ml) at
0.degree. C. was added 4-(chlorosulphonyl) phenyl isocyanate (38.6
mmol, 8.4 g). The reaction mixture was stirred for 20 mins until a
clear solution had formed, and 1:1 water:trifiuoroacetic acid (100
ml total) was added. Vigorous stirring was continued for 16h., the
layers separated, the organic layer was diluted with ethyl acetate
(500 ml) and washed with saturated sodium bicarbonate solution
(4'50 ml), brine (50 ml), dried with anhydrous magnesium sulphate,
and concentrated in vacuo. Column chromatrography (eluant 3
hexane/1 ethyl acetate) yielded the title compound as pale yellow
crystals (8.8 g, 67%).
EXAMPLE 25 ##STR39##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(hexyl
a minocarbonylamino)benzenesulfonamide
To a solution of 302 mg (0.845 mmol) of the product from Example 18
and 137 mL (1.69 mmol) of pyridine in 10 mL of methylene chloride
was added 296 mg (0.928 mmol) of
4-(hexylaminocarbonylamino)benzenesulfonyl chloride from Example 3.
The reaction was stirred for 12 h then the solvent removed in
vacuo. Hash chromatography (silica gel, 6% methanol, 0.5%
ammonia-methylene chloride) afforded 468 mg (87%) of the
BOC-protected title compound.
A solution of 468 mg (0.731 mmol) of BOC-protected tire compound in
5 mL of methylene chloride and 5 mL of trifluoroacetic acid was
stirred for 30 min then the volatile components removed in vacuo.
The residue was azeotroped twice with 10% methanol/toluene, twice
with methanol, then dried in vacuo to give 521 mg (93%) of the
title compound as its trifluroracetate salt: .sup.1 H NMR (400 MHz,
CD.sub.3 OD) .delta. 8.88 (s, 1H), 8.79 (d, 1H, J=5.5 Hz), 8.53 (d,
1H, J=8.2 Hz), 7.99 (m, 1H), 7.59 (dd, 2H, J=6.9, 1.9 Hz), 7.43
(dd, 2H, J=6.9, 1.9 Hz), 7.15 (dd, 2H, J=8.6, 2.1 Hz ), 7.08 (dd,
2H, J=8.6, 2.1 Hz), 5.23 (m, 1H), 3.40-3.10 (m, 6H), 2.94 (m, 2H),
1.49 (m, 2H), 1.32 (m, 6H), 0.90 (m, 2H).
EXAMPLE 26 ##STR40##
(N)-[4-[2-[(phenylmethoxycarbonyl)amino]ethyl]phenyl]-4-cyanobenzensulfona
m ide
Following the procedure outlined in Example 4, the title compound
was prepared from 2-(4-aminophenyl)ethylcarbamic acid phenylmethyl
ester (see Fisher, et. al., Eur. Pat. Appl. 0 611 003 A1, 1994) and
4-cyanobenzenesulfonyl chloride: .sup.1 H NMR (400 MHz, CD.sub.3
OD) .delta..sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.7.81 (d, 2H,
J=8.7Hz), 7.69 (d, 2H, J=8.7Hz), 7.32 (m, 5H), 7.06 (d, 2H,
J=8.4Hz), 6.96 (d, 2H, J=8.4Hz), 6.75 (s, 1H), 5.06 (s, 2H), 4.71
(t, br, 1H), 3.38 (q, 2H, J=6.9Hz), 2.74 (t, 2H, J=7.0Hz).
EXAMPLE 27 ##STR41##
(N)-[4-[2-[(phenylmethoxycarbonyl)amino]ethyl]phenyl]-4-aminooximidomethyl
) benzensulfonamide
A mixture of the nitrile from Example 26 (2.71 g, 6.23 mmol),
absolute ethanol (65 ml), finely divided K.sub.2 CO.sub.3 (5.17 g,
37.4 mmol), and hydroxylamine hydrochloride (2.17 g, 31.2 mmol) was
refluxed for 6 h. The ethanol was removed under reduced pressure.
The resulting solid was dissolved in ethyl acetate and washed with
water 3 times. The organic phase was concentrated in vacuo to 2.87
g (98%) of the title compound as a white powder which was of
sufficient purity to be used in subsequent steps: 1H NMR (400 MHz,
CD.sub.3 OD) .delta.7.71 (s, 4H), 7.31 (m, 5H), 7.04 (d, 2H,
J=8.4Hz), 6.99 (d, 2H, J=8.4Hz), 5.02 (s, 2H), 3.25 (t, 2H,
J=6.8Hz), 2.67 (t, 2H, J=6.7Hz).
EXAMPLE 28 ##STR42##
(N)-[4-[2-[(phenylmethoxycarbonyl)amino]ethyl]phenyl]-4-[5-(3-cyclopentylp
r opyl)-[1,2,4]-oxadiazol-3-yl]benzensulfonamide
To a solution of compound from Example 27 (0.468 g, 1.00 mmol) in
dry pyridine (5.0 ml) was added 4-cyclopentylbutyryl chloride
(0.175 g, 1.00 mmol). The mixture was refluxed for 3.5 h. The
pyridine was removed under reduced pressure. The resulting residue
was purified by silica gel chromatography (35% ethyl acetate in
hexanes) to give 0.152 g (26%) of the title compound: 1H NMR (400
MHz, CDCL.sub.3) .delta. 8.12 (d, 2H, J=8.7Hz), 7.81 (d, 2H,
J=8.7Hz), 7.31 (m, 5H), 7.03 (d, 2H, J=8.1Hz), 6.97 (d, 2H,
J=8.4Hz), 6.67 (s, 1H), 5.05 (s, 2H), 4.70 (t, br, H), 3.37 (q, 2H,
J=6.5Hz), 2.91 (t, 2H, J=7.6Hz), 2.72 (t, 2H, J=7.0), 1.90-1.70 (m,
5H), 1.65-1.30 (m, 6H), 1.06 (m, 2H).
EXAMPLE 29 ##STR43##
N-[4-(2-aminoethyl)phenyl]-4-[5-(3-cyclopentylpropyl)-[1,2,4]-oxadiazol-3-
y l]benzensulfonamide
A mixture of Cbz amine from Example 28 (0.145 g, 0.246 mmol),
palladium hydroxide on carbon (0.02 g), and glacial acetic acid
(5.0 ml) was hydrogenated for 2 h. The acetic acid was removed
under reduced pressure. The residue was purified by silica gel
chromatography (1:9 of 10% ammonium hydroxide in methanol:methylene
chloride) to give 0.058 g (52%) of the title compound: 1H NMR (400
MHz, CDl.sub.3 OD) .delta. 8.11 (d, 2H, J=8.6Hz), 7.87 (d, 2H,
J=8.5Hz), 7.06 (d, 2H, J=8.6Hz), 7.02 (d, 2H, J=8.7Hz), 2.97 (t,
2H, J=7.5Hz), 2.84 (t, 2H, J=6.9Hz), 2.67 (t, 2H, J=7.5Hz),
1.90-1.75 (m, 5H), 1.70-1.40 (m, 6H), 1.12 (m, 2H).
EXAMPLE 30 ##STR44##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[5-(3-
c yclopentylpropyl)-[1,2,41-oxadiazol-3-yl]benzensulfonamide
To a solution of amine from Example 29 (0.053 g, 0.117 mmol) in dry
methanol (30.0 ml) was added 3-pyridine epoxide from Example 16
(0.021 g, 0.175 mmol). The resulting solution was refiuxed
overnight. After concentration, the residue was purified by silica
gel chromatography (13% methanol in methylene chloride) to give
0.01 g (15%) of the title compound: .sup.1 H NMR (400 MHz, CD.sub.3
OD) .delta. 8.52 (d, 1H, J=l.9Hz), 8.42 (dd, 1H, J-1.5, 4.8Hz),
8.13 (d, 2H, J-8.6Hz), 7.85 (m, 3H), 7.40 (dd, 1H, J=4.8, 7.8Hz),
7.10 (d, 1H, J=8.6Hz), 7.03 (d, 2H, J=8.6Hz), 4.81 (dd, 1H, J=4.9,
8.1Hz), 2.96 (t, 2H, J=7.5Hz), 2.93-2.70 (m, 6H), 1.90-1.72 (m,
5H), 1.68-2.48 (m, 4H), 1.42 (m, 2H), 1.11 (m, 2H). ##STR45##
EXAMPLE 31
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(1-h
ydroxy- 1-hexylheptyl)-5-methyl-[1,2,3
]-triazol-2-yl]benzenesulfonamide and
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4
-(1-(R,S)-hydroxyheptyl)-5-methyl-[1,2,3
]-triazol-2-yl]benzenesulfonamide
To a solution of 180 mg of
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(4-met
hoxycarbonyl-5-methyl-[1,2,3]-triazol-2-yl)benzenesulfonamide
(prepared according to the procedures outlined in examples 14-25)
in 2 mL of distilled THF under argon at 0.degree. C. was added,
dropwise, 2 mL of a 2.0M solution of n-hexylmagnesium bromide in
ether. After 5 min, the reaction was quenched with cautious
addition of 5 mL of aqueous ammonium chloride followed by ethyl
acetate extraction of the aqueous layer. The combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo to yield the crude products. Preparative layer
chromatography (PLC) on 2.times.0.5 mm thick silica gel plates
eluted in 9:1 (v/v) dichloromethane:methanol gave two bands A (20
mg) and B (60mg). .sup.1 H NMR (500 MHz, CD.sub.3 OD) of A:
.delta.8.51 (d, 1H, J=2 Hz), 8.41 (dd, 1H, J=1.5, 5 Hz), 8.01 (dd,
2H, 3=2.5, 6.5Hz), 7.81 (m, 1H), 7.78 (dd, 2H, J=2.0, 9.0 Hz), 7.37
(m, 1H), 7.07;7.02 (ABq, 4H, Jab=8.5 Hz), 4.86 (s, CD3OH), 4.79
(dd, 1H, J=7.5, 8 Hz), 2.9-2.7 (m, 6H), 2.44 (s, 3H), 1.85 (m, 4H),
1.40-1.15 (m, 16H), 0.83 (t, 6H, J=7 Hz) indicating the dihexyl
tertiary alcohol adduct, mass spec. expected 677 found 677. .sup.1
H NMR (500 MHz, CD.sub.3 OD) of B: 8.51 (d, 1H, J=2 Hz), 8.41 (dd,
1H, J=l.5, 5 Hz), 8.03 (d, 2H, J=9 Hz), 7.78 (d, 2H, J=9 Hz), 7.37
(dd, 1H, J=4.8, 7.7 Hz), 7.07;7.02 (ABq, 4H, Jab=8 Hz), 4.86 (s,
CD3OH), 4.80 (m, 2H), 2.9-2.7 (m, 6H), 2.38 (s, 3H), 1.87 (m, 2H),
1.44 (m, 1H), 1.4-1.2 (m, 7H), 0.87 (t, 3H, J=7 Hz) indicating the
mono-hexyl adduct. Mass spec expected 591 (for the hexyl ketone)
found 593 (hexyl alcohol, intermediate ketone reduced by Grignard
reagent in situ).
Following the procedures outlined for Examples 14-31, the compounds
listed in Table 2 were prepared. The preparation of compounds of
Examples 70, 73 and 80 is also provided in more detail herein
below.
TABLE 2 ______________________________________ ##STR46## Ex- am-
ple R Selected .sup.1 H NMR (CD.sub.3 OD)
______________________________________ Data 32 4-isopropylphenyl
7.64(d, 2H, J=8.0Hz), 7.33(d, 2H, J=8.0Hz), 4.80(m, 1H), 2.95-
2.70(m, 7H), 1.22(d, 6H, J=6.7Hz) 33 4-iodophenyl, 7.84(d, 2H,
J=8.6Hz), 7.47(d, bistrifluoroacetate salt 2H, J=8.6Hz), 5.19(dd,
1H, J= 10.1, 3.0Hz), 3.40-3.20(m, 4H), 2.96(m, 2H) 34 2-naphthyl
8.28(s, 1H), 7.94(m, 3H), 7.72 (dd, 1H, J=8.7, 1.9Hz), 7.60(m, 2H)
35 3-quinolinyl, 9.01(d, 1H, J=2.3Hz), 8.76(d, bistrifluoroacetate
salt 1H, 1.8Hz), 8.08(d, 1H, J=8.7 Hz), 8.04(d, 1H, J=8.0Hz), 7.93
(m, 1H), 7.73(m, 1H) 36 4-[(N-hexyl,N-methyl- 5.12(d, 1H, J=8.7Hz),
3.40-3.10 aminocarbonyl)- (m, 6H), 2.99(s, 3H), 2.95(m, 2H),
amino]phenyl, 1.56(m, 2H), 1.31(m, 6H), 0.88 bistrifluoroacetate
salt (m, 3H) 37 4-(3-hexyl-2- 5.15(m, 1H), 3.85(m, 2H), 3.53
imidazolidinon-1- (m, 2H), 3.40-3.15(m, 6H), 2.94 yl)phenyl, (m,
2H), 1.55(m, 2H), 1.32(m, bistrifluoroacetate salt 6H), 0.89(m,
3H). 38 4-[(1-oxoheptyl)- 2.35(tr, 2H, J=7.5Hz), 1.65 amino]phenyl,
(quint., 2H, J=7.1Hz), 1.32(m, bistrifluoroacetate salt 6H),
0.892(tr, 3H, J=6.8Hz). 39 4-[(1-oxo-4-phenyl- 7.34-7.25(m, 4H),
7.15-7.05(m, butyl)amino]phenyl, 5H), 2.71(tr, 2H, J=7.7Hz), 2.36
bistrifluoroacetate salt (tr, 2H, J-7.4Hz), 1.96(m, 2H). 40
4-[(propoxycarbonyl)- 4.07(tr, 2H, J=6.6Hz), 1.67 amino]phenyl
(sextet, 2H, J=7.0Hz).0.968(tr, 3H, J=7.4Hz). 41 4-[[[(fur-2-
7.40(d, 1H, J=0.9Hz), 6.32(dd, ylmethyl)amino]car- 1H, J=2.9,
1.8Hz), 6.23(d, 1H, J= bonyl]amino]phenyl, 2.9Hz), 4.34(s, 2H)
bistrifluoroacetate salt 42 4-[[[(2- 7.38-7.02(m, 9H), 3.50-3.15(m,
phenylethyl)amino]- 6H), 2.80(m, 2H) carbonyl]amino]- phenyl,
bistrifluoroacetate salt 43 4-[[[(2-indol-3- 7.58-7.53(m, 3H),
7.42-7.30(m, ylethyl)amino]carbon- 4H), 7.08-6.94(m, 7H), 3.48(tr,
2H, yl]amino]phenyl J=6.9Hz) 2.94(tr, 2H, J=6.8Hz). 44 4- 2.94(m,
2H), 1.51(tr, 2H, J=6.8Hz), [[(octylamino)car- 1.30(m, 10H),
0.884(tr, 3H, bonyl]amino]phenyl, J=6.9Hz). bistrifluoroacetate
salt 45 1- 7.83(d, 2H, J=9.2Hz), 7.48(m, [(hexylamino)car- 2H),
3.92(t, 2H, J=8.8Hz), 3.1- bonyl]indolin-5-yl 3.2(two overlap-ping
t, 4H), 1.54 (m, 2H), 1.30(m, 6H), 0.90(t, 3H, J=6.8Hz). 46 1-
7.83(d, 2H, J=9.2Hz), 7.48(m, [(octylamino)car- 2H), 3.92(t, 2H,
J=8.8Hz), 3.1- bonyl]indolin-5-yl 3.2(two overlap-ping t, 4H), 1.63
(m, 2H), 1.30(m, 10H), 0.89(t, 3H, J=6.9Hz). 47 1-[(N-methyl-N-
7.53(m, 2H), 6.90(d, 1H, J=8.3 octylamino)carbonyl]- Hz), 3.89(t,
2H, J=8.4Hz), 3.26 indolin-5-yl (t, 2H, J=7.6Hz), 3.04(t, 2H, J=
8.4Hz), 2.91(s, 3H), 1.60(m, 2H), 1.27(m, 10H), 0.87(t, 3H, J=6.8).
48 1-(1-oxononyl)indolin- 7.49(m, 2H), 8.09(d, 1H, J=9.1), 5-yl
4.04(t, 2H, J=8.5), 3.07(t, 2H, J=8.5), 2.41(t, 2H, J=7.5), 1.62(m,
2H), 1.30(m, 10H), 0.88(t, 3H, J=6.8) 49 1-(4-methylthiazol-2-
7.87(d, 1H, J=8.6Hz), 7.58(1H, yl)indolin-5-yl dd, J=2.0, 8.6Hz),
7.52(d, 1H, J= 2.0Hz), 6.48(s, 1H), 4.08(t, 2H, J=8.7Hz), 3.25(t,
2H, J=8.7Hz), 2.30(s, 3H). 50 1-(4-octylthiazol-2- 7.97(d, 1H,
J=8.6Hz), 7.57(1H, yl)indolin-5-yl dd, J=2.0, 8.6Hz), 7.53(d, 1H,
J= 2.0Hz), 6.49(s, 1H), 4.06(t, 2H, J=8.8Hz), 3.24(t, 2H, J=8.8Hz),
2.62(t, 2H, J=7.5Hz), 1.68(m, 2H), 1.2-1.4(m, 10H), 0.88(t, 3H,
J=7.0Hz). 51 1-(4-ethyl-5- 7.87(d, 1H, J=8.5Hz), 7.54(1H,
methylthiazol-2- dd, J=2.0, 8.5Hz), 7.50(d, 1H, J= yl)indolin-5-yl
2.0Hz), 4.02(t, 2H, J=8.7Hz), 3.20(t, 2H, J=8.7Hz), 2.56(q, 2H,
J=7.7Hz), 2.26(s, 3H), 1.20 (t, 3H, J=7.7Hz). 52 4-(3-octyl-2-
4.78(m, 1H), 3.83(m, 2H), 3.52 imidazolidinon-1- (m, 2H), 3.24(t,
2H, 8Hz), 1.60- yl)phenyl 1.51(m, 2H), 1.35-1.25(m, 10H), 0.88(t,
2H, 8Hz). 53 4-[3-(4,4,4- 3.86(m, 2H), 3.54(m, 2H), 3.40-
trifluorobutyl)-2- 3.20(m, 6H), 2.19(m, 2H), 1.82 imidazolidinon-1-
(quin, J=7.9Hz, 2H) yl]phenyl, bistrifluoroacetate salt 54
4-[3-(3-phenylpropyl)- 7.20(m, 4H), 7.10(m, 1H), 5.15
2-imidazolidinon-1- (dd, 1H, 9.6, 4Hz), 3.75(m, 2H), yl]phenyl,
3.46(m, 2H), 3.36-3.20(m, 6H), bistrifluoroacetate salt
2.95-2.91(m, 2H), 2.65(t, 2H, 8Hz), 1.90(qu, 2H, 8Hz). 55
4-[3-(4,4,5,5,5- 3.87(m, 2H), 3.56(m, 2H), 3.40-
pentafluoropentyl)-2- 3.20(m, 6H), 2.14(m, 2H), 1.86
imidazolidinon-1- (quin, J=7.8Hz, 2H) yl]phenyl,
bistrifluoroacetate salt 56 4-[3-(2- 3.82(m, 2H), 3.50(m, 2H),
2.87- cyclohexylethyl)-2- 2.70(m, 6H), 1.78-1.63(m, 5H),
imidazolidinon-1- 1.41(quartet, 2H, J=7.2Hz), 1.30- yl]phenyl,
1.18(m, 4H), 0.949(m, 2H). bistrifluoroacetate salt 57 4-[3-[3-(4-
7.19(s, 4H), 4.79(m, 1H), 3.74(m, chlorophenyl)propyl]- 2H),
3.47(m, 2H), 3.30(m, 2H), 2-imidazolidinon-1- 2.63(t, 2H, 7.6Hz),
1.91-1.83(m, yl]phenyl 2H). 58 4-(3-pentyl-2- 3.82(m, 2H), 3.53(m,
2H), 2.94 imidazolidinon-1- (m, 2H), 1.57(quintet, 2H, J=7.4
yl)phenyl, Hz), 1.39-1.28(m, 4H), 0.916, (tr, bistrifluoroacetate
salt 3H, J=7.1Hz). 59 4-[3-(3- 3.81(m, 2H), 3.51(m, 2H), 3.23(t,
cyclopentylpropyl)-2- J=7.3Hz, 2H), 1.78(m, 3H), 1.57
imidazolidinon-1- (m, 6H), 1.33(m, 2H), 1.17(m, yl]phenyl 2H) 60
4-[3-(2- 3.83(m.2H), 3.53(m, 2H), 2.94 cyclopentylethyl)-2- (m,
2H), 1.81(m, 4H), 1.65-1.53 imidazolidinon-1- (m, 5H), 1.16(m, 2H).
yl]phenyl, bistrifluoroacetate salt 61 4-[3-(3- 3.83(m, 2H),
3.51(m, 2H), 3.22(t, cyclohexylpropyl)-2- J=7.3Hz, 2H), 1.71(m,
5H), 1.56 imidazolidinon-1- (m, 2H), 1.20(m, 6H), 0.88(m, yl]phenyl
2H) 62 4-[3-(2,2- 3.82(m, 2H), 3.60(m, 2H), 3.03(s,
dimethylhexyl)-2- 2H), 1.28(m, 6H), 0.93(m, 3H), imidazolidinon-1-
0.91(s, 6H) yl]phenyl 63 4-(3-hexyl-2- 6.93(d, 1H, 4Hz), 6.70(d,
1H, imidazolon-1-yl)- 4Hz), 4.79(m, 1H), 3.64(t, 2H, phenyl 8Hz),
1.71-1.64(m, 2H), !.35-1.28 (m, 6H), 0.91-0.86(m, 3H). 64
4-[3-(4,4,4- 6.97(d, 1H, 3Hz), 6.73(d, 1H, trifluorobutyl)-2- 3Hz),
3.73(t, 2H, 7Hz), 2.23-2.19 imidazolon-1-yl]phenyl (m, 2H),
1.98-1.92(m, 2H). 65 4-(3-octyl-2- 6.93(d, 1H, 4Hz), 6.69(d, 1H,
imidazolon-1-yl)- 4Hz), 3.64(t, 2H, 7Hz), 1.70-1.63 phenyl (m, 2H),
1.33-1.23(m, 10H), 0.90- 0.85(m, 3H). 66 4-[3-(3- 6.93(d, 1H, 3Hz),
6.69(d, 1H, cyclopentylpropyl)-2- 3Hz), 3.63(t, 2H, 7Hz), 1.80-1.47
imidazolon-1-yl]phenyl (m, 11H), 1.35-1.29(m, 2H), 1.13- 1.02(m,
2H). 67 4-(2-octyl-3-oxo- 8.25(s, 1H), 3.79(t, 2H, 7Hz),
[1,2,4]-triazol-4- 1.80-1.70(m, 2H), 1.36-1.25(m, yl)phenyl 10H),
0.91-0.86(m, 3H). 68 4-(4-hexyl-5- 3.98(t, 2H, J=7.1Hz), 2.9-2.7(m,
tetrazolon-1-yl)phenyl 6H), 1.82(q, 2H, J=7Hz), 1.4-1.27 (m, 6H),
0.89(t, 3H, J=7Hz) 69 4-(4-octyl-5-tetra- 3.98(t, 2H, J=7.1Hz),
2.9-2.7(m, zolon-1-yl)phenyl 6H), 1.83(m, 2H), 1.4-1.2(m, 10H),
0.87(t, 3H, J=7Hz) 70 4-[4-(3- 3.97(t, 2H, J=7.1Hz), 2.9-2.7(m,
cyclopentylpropyl)-5- 6H), 1.9-1.7(m, 5H), 1.6(m, 1H),
tetrazolon-1-yl]phenyl 1.5(m, 1H), 1.37(m, 2H), 1.07(m, 2H) 71
4-(2-pentyloxazol-5- 7.48(s, 1H), 4.82(m, 1H), 2.92- yl)phenyl
2.70(m, 8H), 1.80(m, 2H), 1.39 (m, 4H), 0.92(m, 4H) 72
4-(2-octyloxazol-5- 7.52(s, 1H), 5.09(m, 1H), 3.01- yl)phenyl
2.82(m, 8H), 1.77(m, 2H), 1.37- 1.27(m, 10H), 0.87(m, 1H) 73
4-[2-(2- 7.52(s, 1H), 4.80(m, 1H), 2.94- cyclopentylethyl)-
2.70(m, 8H), 1.79(m, 5H), 1.62 oxazol-5-yl]phenyl (m, 2H), 1.54(m,
2H), 1.12(m, 2H) 74 4-[(4-ethyl-5- 7.62(d, 2H, J=9Hz), 7.58(d, 2H,
methylthiazol-2- J=9Hz), 2.53(q, 2H, J=7.5Hz), yl)amino]phenyl
2.23(s, 3H), 1.18(t, 3H, J=7.5 Hz) 75 4-[(4,5,6,7- 7.54(d, 2H,
J=9Hz), 7.48(d, 2H, tetrahydrobenzo- J=9Hz), 2.54(m, 2H), 2.50(m,
thiazol-2- 2H), 1.75(m, 4H) yl)amino]phenyl 76
4-(2-hexylimidazol-4- 7.75(s, 1H), 5.04(m, 1H), 3.29- yl)phenyl
3.20(m, 4H), 2.97-2.90(m, 4H), 1.82(m, 2H), 1.40-1.30(m, 6H),
0.9(m, 3H) 77 4-(1-methyl-2- 7.92(s, 1H), 5.30(m, 1H), 4.84(s,
octylimidazol-5-yl)- 3H), 3.48-3.25(m, 4H), 3.05-2.95 phenyl (m,
4H), 1.80(m, 2H), 1.50-1.26 (m, 10H), 0.89(m, 3H) 78
4-[1-methyl-2-(2- 7.41(s, 1H), 3.64(s, 3H), 2.96-2.68
cyclopentylethyl)- (m, 8H), 1.90-1.79(m, 9H), 1.16
imidazol-5-yl]phenyl (m, 2H) 79 4-[1-methyl-2-[2-(4- 7.40(s, 1H),
7.10-6.95(m, 4H), fluorophenyl)ethyl]- 4.91(m, 1H), 3.39(s, 3H),
3.0(bs, imidazol-5-yl]phenyl 4H) 80 4-(5-pentyl-[1,2,4]- 2.96(t,
2H, J=7.6Hz), 1.84(t, 2H, oxadiazol-3-yl)phenyl J=7.4Hz), 1.39(m,
4H), 0.92(t, 3H, J=7.1) 81 4-[5-(2- 2.98(t, 2H, J=7.5Hz), 1.84(m,
5H), cyclopentylethyl)- 1.70-1.50(m, 4H), 1.16(m, 2H)
[1,2,4]-oxadiazol-3- yl]phenyl 82 4-(5-hexyl-[1,2,4]- 2.96(t, 2H,
J=7.5Hz), 1.84(quin, oxadiazol-3-yl)phenyl 2H, J=7.4Hz),
1.48-1.28(m, 6H), 0.90(t, 3H, J=7.0Hz) 83 4-(5-heptyl-[1,2,4]-
2.96(t, 2H, J=7.5Hz), 1.84(quin, oxadiazol-3-yl)phenyl 2H,
J=7.0Hz), 1.46-1.26(m, 8H), 0.89(t, 3H, J=6.9Hz) 84
4-(5-hexylthio-[1,2,4]- 3.11(t, 2H, J=7.3Hz), 2.98-2.84
triazol-3-yl)phenyl (m, 4H), 2.76(t, 2H, J=7.3Hz), 1.65 (q, 2H,
J=7.3Hz), 1.37 (q, 2H, J=7.1Hz), 1.28-1.23(m, 4H), 0.84(t, 3H,
J=6.9Hz) 85 4-[[4-(4- 8.84(s, 1H), 8.75(d, 1H, J=5.07Hz),
propylpiperidin-1-yl)- 8.46(d, 1H, J=8Hz), 7.15 &
1,1-dioxo-[1,2,5]- 7.08 each(d, 2H, J=8Hz), 0.92(t, thiadiazol-3-
3H, J=7Hz) yl]amino]phenyl 86 4-[[4- 7.15(d, 2H, J=8.5Hz), 7.12(d,
2H, (hexylmethylamino)- J=8.5Hz), 5.19(dd, 1H, 3.1Hz,
1,1-dioxo-[1,2,5]- 9Hz), 2.93(m, 2H), 0.90(t, 3H, thiadiazol-3-
6.8Hz) yl]amino]phenyl 87 4-[[4- 7.16(d, 2H, J=8.8Hz), 7.11(d, 2H,
(heptylmethylamino)- J=8.8Hz), 5.01(dd, J=3.2Hz, 1,1-dioxo-[1,2,5]-
9.9Hz), 2.92(m, 2H), 1.68(m, 2H) thiadiazol-3- yl]amino]phenyl 88
4-(1-octyl-2,4- 4.09(s, 2H), 3.41(t, 2H, 7hz), imidazolidinedion-3-
1.65-1.56(m, 2H), 1.30-1.25(m, yl)phenyl 10H), 0.91-0.86(m, 3H). 89
4-[3-(3-nitrophenyl)-5- 8.55(t, 1H, J=1.9Hz), 8.47(d,
pyrazolon-1-yl]phenyl 1H, J=2.0Hz), 8.37(dd, 1H, J=3.2Hz), 8.14(d,
2H, J=8.9Hz), 8.08(t, 2H, J=8.5Hz), 7.74(d, 3H, J=8.9Hz), 7.56(t,
1H, J= 8.0Hz), 7.33(dd, 1H, J=4.8Hz), 7.04 (dd, 4H, J=6.6Hz),
4.75(t, 1H, J=2.1Hz), 2.83-2.69(m, 6H)
______________________________________
EXAMPLE 70 ##STR47##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-
c yclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide
A. Preparation of 3-Cyclopentyl-1-Iodopropane
To a solution of 5 g of commercially available
3-cyclopentyl-1-propanol in 20 mL of dichloromethane at 0.degree.
C. was added 5 mL of dry triethylamine and 5 g of methanesulfonyl
chloride. The mixture containing a heavy white precipitate of
triethylamine hydrochloride was stirred an additional 5 min before
70 mL of diethyl ether was added. The mixture was filtered through
a glass fritted funnel to remove the precipitate and the tiltrate
was concentrated in vacuo to afford the mesylate. To this was added
10 g of sodium iodide and 30 mL of acetone. After 18 h at room
temperature, the dark slurry was dissolved in water and extracted
with dichloromethane. The extracts were combined and washed with
excess aqueous sodium sulfite and dried over magnesium sulfate.
Filtration and concentration of the dichloromethane solution gave 8
g of the title compound: .sup.1 H NMR (CDCl.sub.3) .delta.5 3.19
(t, 2H, J=7.1 Hz), 1.85 (m, 3H), 1.77 (m, 2H), 1.61 (m, 2H), 1.52
(m, 2H), 1.41 (m, 2H), 1.09 (m, 2H).
B. Preparation of
4-(3-Cyclopentylpropyl)-1-Phenyl-5-Tetrazolone
To a solution of 600 mg of 1-phenyl-5-tetrazolone (for the
synthesis of this compound see: Horwitz, J. P.; Fisher, B. E.;
Tomasewski, A. J. J Amer Chem Soc 1959, 81, 3076) in 2 mL of
N,N-dimethylformamide (DMF) was added 280 mg of powdered 85%
potassium hydroxide followed by 870 mg of
3-cyclopentyl-1-iodopropane from Step A. The mixture was stirred at
80.degree. C. for 18 h and then quenched by addition of water. The
product was extracted with dichloromethane and purification by
flash chromatography on silica gel (9:1 hexane:ethyl acetate)
afforded 830 mg of the title compound: .sup.1 H NMR (CDCl.sub.3)
.delta.7.96 (d, 2H, J=8.5 Hz), 7.50 (t, 2H, J=7.5 Hz), 7.37 (t, 1H,
J=7.5 Hz), 4.02 (t, 2H, J=7.1 Hz), 1.90 (m, 3H), 1.79 (m, 2H), 1.61
(m, 2H), 1.53 (m, 2H), 1.41 (m, 2H), 1.10 (m, 2H).
C. Preparation of
4-(3-cyclopentylpropyl)-1-(4-nitrophenyl)-5-tetrazolone
To a solution of 7 g of
4-(3-cyclopentylpropyl)-1-phenyl-5-tetrazolone from Step B in 50 mL
of dry acetonitrile was added, in one portion, 4.2 g of 95%
nitronium tetrafluoroborate with rapid stirring. The reaction
mixture was stirred at room temperature for 30 min before an
additional 2 g of nitronium tetrafluoroborate was added to react
with detectable starting material. The mixture was stirred an
additional 30 min before addition of water and extraction with
ethyl acetate. The combined ethyl acetate extracts were washed with
aqueous sodium bicarbonate and dried over magnesium sulfate.
Filtration and concentration of the filtrate gave an orange oil.
Flash chromatographic separation on silica gel using 4:1
hexane:ethyl acetate afforded 4.6 g of the para-nitrophenyl title
compound as a solid (Rf=0.7) and 2 g of the ortho-nitrophenyl
product as an oil (Rf=0.2): Para-nitro product .sup.1 H NMR
(CDCl.sub.3) .delta.8.35 (ABq, 4H, Jab=9.3 Hz), 4.06 (t, 2H, J=7.1
Hz), 1.93 (m, 3H), 1.80 (m, 2H), 1.63 (m, 2H), 1.54 (m, 2H), 1.43
(m, 2H), 1.10 (m, 2H); Ortho-nitro product 1H NMR (CDCl.sub.3)
.delta.5 8.13 (dd, 1H, J=1.1, 8.3 Hz), 7.81 (dt, 1H, J=1.3, 7.8
Hz), 7.72 (dd, 1H, J=1.1, 8.0 Hz), 7.67 (dt, 1H, J=l.4, 7.6 Hz),
4.03 (t, 2H, J=7.1 Hz), 1.92 (m, 3H), 1.80 (m, 2H), 1.61 (m, 2H),
1.53 (m, 2H), 1.42 (m, 2H), 1.10 (m, 2H).
D. Preparation of
1-(-Aminophenyl)-4-(3-Cyclopentylpropyl)-5-Tetrazolone
To a solution of 6.23 g of
4-(3-cyclopentylpropyl)-1-(4-nitrophenyl)-5-tetrazolone from Step C
in 250 mL of ethanol was added 1.8 g of 10% palladium on carbon.
The mixture was stirred under a 1 atmosphere pressure of hydrogen
provided by a balloon for 3-6 h. The catalyst was then removed by
filtration through a plug of silica gel. The tiltrate was
concentrated in vacuo to yield 5.52 g of the title compound as a
waxy solid: .sup.1 H NMR (CDCl.sub.3) .delta.5 7.64 (d, 2H, J=8.9
Hz), 6.77 (d, 2H, J=8.9 Hz), 4.01 (t, 2H, J=7.3 Hz), 3.83 (br s,
2H), 1.90 (m, 3H), 1.79 (m, 2H), 1.60 (m, 2H), 1.54 (m, 2H), 1.41
(m, 2H), 1.10 (m, 2H).
E. Preparation of
4-[4-(3-Cyclopentylpropyl)-5-Tetrazolon-1-Yl]-Benzenesulfonyl
Chloride
To a solution of 32 mL of concentrated hydrochloric acid and 8 mL
of glacial acetic acid at -20.degree. C. was added 5.42 g of
powdered 1-(4-aminophenyl)-4-(3-cyclopentylpropyl)-5-tetrazolone
from Step D. The mixture was stirred for 5 min before a solution of
1.6 g of sodium nitrite in 10 mL of water was added at a rate which
kept the temperature from rising above -10.degree. C. The diazonium
salt mixture was stirred an additional 40 min at -20.degree. C. and
then added in one portion to a solution of 32 mL of glacial acetic
acid containing 690 mg of copper (I) chloride saturated with sulfur
dioxide at 0.degree. C. The resultant reaction mixture instantly
changed in color from a dark green with nitrogen evolution to a
lime green slurry as time progressed. The reaction mixture was
allowed to warm from 0.degree. C. to room temperature over 50 min.
The mixture was then poured into ice-water and extracted with ethyl
acetate. The combined organic extracts were washed once with cold
water, dried over magnesium sulfate, filtered, and concentrated in
vacuo to remove acetic acid. The crude sulfonyl chloride was
purified by flash chromatography (silica gel, dichloromethane) to
yield 3.4 g of the title compound as a white solid: 1H NMR
(CDCl.sub.3) .delta.8.37 (d, 2H, J=9.1 Hz), 8.20 (d, 2H, J=8.6 Hz),
4.06 (t, 2H, J=7.1 Hz), 1.93 (m, 3H), 1.81 (m, 2H), 1.62 (m, 2H),
1.55 (m, 2H), 1.41 (m, 2H), 1.11 (m, 2H).
F. Preparation of
(R)-N-[4-[2-[N-(1,1-Dimethylethoxycarbonyl)-N-[2-Hydroxy-2-(Pyridin-3-Yl)E
thyl]Amino]Ethyl]Phenyl]-4-[4-(3-Cyclopentylpropyl)-5-Tetrazolon-1-Yl]Benze
nesulfonamide
To 2.84 g of the product from Example 18 was added 30 mL of
dichloromethane and 3.01 g of
4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonyl
chloride from Step E followed by 5 mL of dry pyridine. The orange
solution was stirred at room temperature for 12 h and TLC showed no
starting material left. The mixture was concentrated to dryness and
the residual solid foam was taken up in dichloromethane and
purified by flash chromatography on silica gel (4:6 acetone:hexane)
3 times to obtain 3.1 g of the title compound: 1H NMR (CD.sub.3 OD)
.delta.8.46 (d, 1H, J=9.2 Hz), 8.41 (m, 1H, J=4.8 Hz), 8.07 (d, 2H,
J=6.9 Hz), 7.86 (d, 2H, J=8.3 Hz), 7.80 (dd, 1H, J=6.9, 24.3 Hz),
7.40 (m, 1H, J=5.5 Hz), 7.02 (m, 4H), 4.85 (m, 1H), 4.01 (t, 2H,
J=7.1 Hz), 3.43-3.10 (m, 4H), 2.72 (m, 2H), 1.87 (m, 3H), 1.78 (m,
2H), 1.62 (m, 2H), 1.53 (m, 2H), 1.30 (d, H), 1.10 (m, 2H).
G. Preparation of
(R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]-ethyl]phenyl]-4-[4-(3
-cyclopentylpropyl)-5-tetrazolon- 1-yl]benzene-sulfonamide
A 3.1-g sample of Boc derivative from Step F was dissolved in 50 mL
of methanol and 10 mL of concentrated hydrochloric acid. The
solution was heated at 50.degree. C. for 1 h. A precipitate of the
hydrochloride salt was obtained. This was cooled and basified with
excess sodium bicarbonate solution and extracted with ethyl
acetate. The combined extracts were dried over sodium sulfate,
filtered, and concentrated in vacuo. The residual solid was
purified by flash chromatography (silica gel, 9:1
dichloromethane:methanol) to yield 2.37 g of the title compound as
a glass: .sup.1 H NMR (CD.sub.3 OD) 15 8.51 (d, 1H, J=2.1 Hz), 8.42
(dd, 1H, J=1.6, 4.8 Hz), 8.09 (d, 2H, J=8.9 Hz), 7.86 (d, 2H, J=8.7
Hz), 7.81 (d, 1H, J=7.7 Hz), 7.39 (dd, 1H, J=4.6, 7.8 Hz), 7.05
(ABq, 4H, Jab=8.5 Hz), 4.79 (m, H), 3.97 (t, 2H, J=7.1 Hz),
2.90-2.70 (m, 6H), 1.90-1.74 (m, 5H), 1.61 (m, 2H), 1.53 (m, 2H),
1.37 (m, 2H), 1.07 (m, 2H).
EXAMPLE 70A ##STR48##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-
c yclopentylpropyl)-5-tetrazolono 1-yl]benzenesulfonamide
dihydrochoride
To 1.56 g of
(R)-N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-
cyclopentylpropyl)-5-tetrazolon-1-yl]benzenesulfonamide, the free
base from Example 70, was added 75 mL of methanol and 3 mL of 2 N
hydrochloric acid. The solution was concentrated to dryness in
vacuo and the residual salt was redissolved in 30 mL of methanol
and 100 mL of boiling ethanol. Upon cooling (ice bath),
crystallization occurred to afford 1.15 g of the title compound as
a white crystalline solid: mp 198.degree.-202.degree. C. (decomp.);
.sup.1 H NMR (CD.sub.3 OD) .delta.8.99 (br s, 1H), 8.86 (d, 1H,
J=5.5 Hz), 8.74 (d, 1H, J=8.0Hz), 8.14 (dd, 1H, J=5.5, 8.0 Hz),
8.08 (d, 2H, J=9 Hz), 7.89 (d, 2H, J=9 Hz), 7.15 (ABq, H, Jab=8.4
Hz), 5.35 (dd, 1H, J=2.5, 9.5 Hz), 4.00 (t, 2H, J=7.1 Hz), 3.47
(dd, 1H, J=3.0, 12.8 Hz), 3.35-3.22 (m, 3H), 2.99 (m, 2H), 1.87 (m,
3H), 1.79 (m, 2H), 1.61 (m, 2H), 1.53 (m, 2H), 1.39 (m, 2H), 1.10
(m, 2H).
EXAMPLE 73 ##STR49##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[2-(2-
c yclopentylethyl)oxazol-5-yl]benzenesulfonamide
A. Preparation of 2-Azido-1-Phenylvinyl 3-Cyclopentylpropionate
To a stirred solution of .alpha.-azidoacetophenone (3.37 g, 20.9
mmol) in dry THF (50 mL) was added a solution of LDA (2.0 M in
cyclohexane, 12.5 mL, 25 mmol) at -78.degree. C. under nitrogen
dropwise. After the reaction mixture was stirred for 1 h, a
solution of 3-cyclopentylpropionyl chloride (5.04 g, 31.35 mmole,
1.5 eq.) was added to the dark red mixture, and after 10 min, the
mixture was slowly warmed to room temperature. Stirring was
continued for 1 h and the resultant yellow mixture was poured into
water and extracted with ethyl acetate (3.times.50 mL). The
combined organics were washed with water and brine, dried over
magnesium sulfate, and filtered. Evaporation of solvent followed by
column chromatography on silca gel (eluent: 2:1 ethyl
acetate:hexanes) gave 4.0 g (71.5%) of the title compound: .sup.1 H
NMR (400 MHz, CDCl.sub.3) .epsilon. 7.32-7.26 (m, 5H), 6.53 (s,
1H), 2.58 (t, 2H, J=7.5 Hz), 1.89-1.70 (m, 5H), 1,65-1.40 (m, 4H),
1.2 (m, 2H).
B. Preparation of 2-(2-Cyclopentylethyl)-5-Phenyloxazole
To a stirred solution of 2-azido-1-phenylvinyl
3-cyclopentylpropionate from Step A (4.0 g, 14 mmol) in dry
cyclohexane (10 mL) was added triethyl phosphite (12 g, 74 mmol)
dropwise. After stirring at room temperature for 1 h, the mixture
was heated at 90.degree. C. in an oil bath under nitrogen for 6 h.
The mixture was cooled and chromatographed on a silica gel column
(eluent: 1:5 ethyl acetate:hexanes) to give 1.57 g (46.6%) of the
title compound as a white solid: .sup.1 H NMR (400 MHz, CDCl.sub.3)
.delta.7.59 (dt, 2H, J=2.0,8.2 Hz), 7.38 (dr, 2H, J=1.4, 8.0 Hz),
7.29 (tt, 1H, J=2.0, 8.0 Hz), 7.19 (s, 1H), 2.82 (t, 2H, 7.5 Hz),
1.89-1.75 (m, 5H), 1.61-1.47 (m, 4H), 1.11 (m, 2H).
C. Preparation of
4-[2-(2-Cyclopentylethyl)Oxazol-5-Yl]Benzenesulfonyl Chloride
Neat chlorosulfonic acid (2 mL) was added to
2-(2-cyclopentylethyl)-5-phenyloxazole from Step B (500 mg, 2.07
mmol) at room temperature under nitrogen with stirring. To this
brown solution was added sodium chloride (100 mg) in portions and
then the mixture was heated at 50.degree. C. in an oil bath. After
2 h at 50.degree. C., the mixture was poured onto ice-water and
extracted with ethyl acetate (3.times.10 mL). The combined organics
were washed with saturated aqueous sodium bicarbonate solution,
water, and brine, dried over sodium sulfate, and evaparated. The
brown residue was chromatogaphed on silica gel (eluent: 2:3 ethyl
acetate:hexanes) to give 500 mg (76.9%) of the title compound as an
off-white solid: 1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (d, 2H,
J=8.2 Hz), 7.81 (d, 2H, J=8.2 Hz), 7.45 (s, 1H), 2.85 (t, 2H, 7.5
Hz), 1.90-1.75 (m, 5H), 1.70-1.48 (m, H), 1.12 (m, 2H).
D. Preparation of
(R)-N-[4-[2-[N-(1,1-Dimethylethoxycarbonyl)-N-[2-Hydroxy-2-(Pyridin-3-Yl)E
thyl]Amino]Ethyl]Phenyl]-4-[2-(2-Cyclopentylethyl)Oxazol-5-yl]Benzenesulfon
amide
To a solution of amine from Example 18 (456 mg, 1.28 mmol) in dry
methylene chloride (10 mL) was added pyridine (316 mg, 4 mmol)
followed by a solution of
4-[2-(2-cyclopentylethyl)oxazol-5-yl]benzenesulfonyl chloride (420
mg, 1.34 mmol) from Step C at room temperature under nitrogen.
After stirring 12 h, the solvent was removed under reduced pressure
and the product was isolated by column chromatography on silica gel
(eluent: 5:95 methanol:methylene chloride) to give 750 mg (88.8%)
of the title compound as a white solid: 1H NMR (400 MHz,
CDCl.sub.3) .delta.8.48 (bs, 2H), 7.72 (d 2H, J=8 Hz), 7.64 (m,
1H), 7.6 (d. 2H, J=8 Hz), 7.3, (s, 1H), 7.26 (m, 1H), 6.98 (bs,
4H), 6.60 (bs, 1H), 4.85 (m, 1H), 3.42-3.20 (m, 4H), 2.8 (t, 2H,
J=7.5 Hz), 2.63 (m, 2H), 1.82-1.76 (m, 5H), 1.62-1.48 (m, 4H), 1.12
(m, 2H).
E. Preparation of
(R)-N-[4-[2-[[2-Hydroxy-2-(Pyridin-3-Yl)Ethyl]Amino]-Ethyl]Phenyl]-4-[2-(2
-Cyclopentylethyl)Oxazol-5-Yl]Benzenesulfonamide
(R)-N-[4-[2-[N-(1,1-dimethylethoxycarbonyl)-N-[2-hydroxy-2-(pyridin-3-yl)et
hyl]amino]ethyl]phenyl]-4-[2-(2-cyclopentylethyl)oxazol_
5-yl]benzenesulfonamide (740 mg, 1.12 mmol) from Step D was treated
with freshly prepared methanolic hydrogen chloride (5 mL)
overnight. The solvent was removed under reduced pressure and the
free base was isolated by column chromatography on silica gel
(eluent: 1:9 10% ammonium hydroxide in methanol:methylene chloride)
to afford the title compound as a white solid (560 mg, 89.3%): 1H
NMR (500 MHz, CD.sub.3 OD) .delta.8.52 (d, 1H, J=2.0 Hz), 8.43 (dd,
1H, J=1.5, 5 Hz), 7.81 (bd, H), 7.77 (d, 2H, J=8.5 Hz), 7.74 (d,
2H, J=8.5 Hz), 7.52 (s, 1H), 7.38 (dd, 1H, J=5, 7.5 Hz), 7.08 (d,
2H, J =8.5 Hz), 7.02 (d, 2H,J=8.5 Hz), 4.80 (m, 1H), 2.94-2.70 (m,
8H), 1.79 (m, 5H), 1.62 (m, 2H), 1.54 (m, 2H), 1.12 (m, 2H).
EXAMPLE 80 ##STR50##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-(5-pen
t yl-[1.2.4]-oxadiazol-3-yl)benzensulfonamide
A. Preparation of
(R)-N-[4-[2-[N-(1,1-Dimethylethoxycarbonyl)-N-[2-Hydroxy-2-(Pyridin-3-Yl)e
thyl]Amino]Ethyl]Phenyl]-4-Cyano-Benzensulfonamide
To a solution of 780 mg (2.18 mmol) of amine from Example in 10 mL
of methylene chloride was added 0.16 mL of pyridine and 450 mg of
4-cyanobenzenesulfonyl chloride. The reaction mixture was stirred
at room temperature overnight. TLC (acetone 25%, methylene chloride
5%) on silica gel indicated the formation of a major fast moving
(rf 0.48) spot. Purification by flash chromatography (silica gel,
25% acetone/dichloromethane) gave 716 mg of the title compound as a
white solid: .sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.8.53-8.44
(m, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.72-7.68 (m, 1H), 7.67 (d, J=8.7
Hz, 2H), 7.3-7.23 (m, 1H), 7.1-6.9 (m, 4H), 4.8 (m, 1H), 3.5-2.6
(m, 6H), 1.42 (s, 9H).
B. Preparation of
(R)-N-[4-[2-[N-(1,1-Dimethylethoxycarbonyl)-N-[2-Hydroxy-2-(Pyridin-3-Yl)E
thyl]Amino]Ethyl]Phenyl]-4-(Aminooximidomethyl)Benzensulfonamide
The cyano compound from Step A (250 mg), 175 mg of hydroxylamine
hydrochloride, and 414 mg of finely ground potassium carbonate were
suspended in 10 mL of ethanol and heated at reflux overnight. TLC
(acetone/methylene chloride 40:60) indicated the formation of a new
low rf product (rf 0.18). The mixture was filtered. The tiltrate
was concentrated to give the title compound, which was used without
further purification: 1H NMR (400 MHz, CDCl.sub.3) .delta.8.42-8.35
(m, 2H), 7.62 (m, 1H), 7.54 (s, 4H), 7.18 (m, 1H), 6.95-6.8 (m,
4H), 5.03 (br s, 2H), 4.73 (m, 1H), 3.25-3.0 (m, 4H), 2.6-2.5 (m,
2H), 1.30 (s, 9H).
C, Preparation of
(R)-N-[4-[2-[[2-Hydroxy-2-(Pyridin-3-Yl)Ethyl]Amino]Ethyl]Phenyl]-4-(5-Pen
tyl-[1,2,4]-Oxadiazol-3-Yl)Benzensulfonamide.
To a solution of 111 mg of amidoxime from Step B in 0.5 mL of
pyridine was added 0.028 mL of hexanoyl chloride. The reaction
mixture was stirred for 1.5 hours. TLC analysis indicated that a
new spot more mobile than the amidoxime formed (rf 0.67, 4:6
acetone:methylene chloride). Stirring was continued overnight until
the reaction was complete by TLC analysis, and then the mixture was
heated at reflux for 2 hours. A new, more mobile spot was evident
by TLC (rf .80, 4:6 acetone:methylene chloride). The pyridine was
distilled off and the residue purified by flash chromatography (4:6
acetone:methylene chloride). The resultant intermediate was
deprotected by stirring with 2 mL of 1:1 TFA/methylene chloride for
30 min. The volatile portion was distilled off and the residue
treated twice with methanol/ammonium hydroxide solution (9/1). The
residue left after evaporation was purified by flash chromatography
on silica gel (90/9/1 methylene chloride-methanol-conc. ammonium
hydroxide) to yield 61.3 mg of the title compound: .sup.1 H NMR
(400 MHz, CD.sub.3 OD) 6 8.51 (d, J=2.0, 1H), 8.42 (dd, J=1.7, 4.9
Hz, 1H), 8.13 (d, J=8.7, 2H), 7.85-7.80 (m, 1H), 7.83 (d, J=8.7,
2H), 7.38 (m, H), 7.09 (d, J=8.6, 2H), 7.02 (d, J=8.6, 2H), 4.79
(m, 1H), 2.96 (t, J=7.6 Hz, 2H), 2.8-2.7 (m, 6H), 1.84 (m, 2H),
1.39 (m, 4H), 0.92 (t, J=7.1 Hz, 3H).
Starting with commercially available (R)-styrene epoxide and
following the procedures outlined for Examples 17,18 and 25, the
compounds listed in Table 3 were prepared.
TABLE 3 ______________________________________ ##STR51## Exam- ple
R Selected .sup.1 H NMR (CD.sub.3 OD)
______________________________________ Data 90 4-iodophenyl,
7.84(d, 2H, J=8.6Hz), 7.45(d, trifluoroacetate salt 2H, J=8.5Hz) 91
2-naphthyl, 8.31(s, 1H), 7.96-7.90(m, 3H), trifluoroacetate salt
7.74(dd, 1H, J=1.8, 8.7Hz), 7.63 (t, 1H), 7.58(t, 1H) 92
3-quinolinyl, 9.01(d, 1H, J=2.2Hz), 8.75(d, trifluoroacetate salt
1H, J=2.1Hz), 8.07(d, 1H, J=8.4 Hz), 8.03(d, 1H, J=8.3Hz), 7.92 (t,
1H, J=7.0Hz), 7.72(t, 1H, J= 7.1Hz)
______________________________________
EXAMPLE 93 ##STR52##
(R)-N-[4-[2-[[2-Hydroxy-2-(pyridin-3-yl)ethyl]amino]-2-methylpropyl]-pheny
l ]-4-(3-hexyl-2-imidazolidinon-1-yl)benzenesulfonamide
A solution of pyridine epoxide (160mg,1.32 mmol) from example 16
and 4-amino-a,a-dimethylphenethylamine (1 .2 g, 7.3 mmol), prepared
according to J. Biol. Chem. 1981, 256, 11944-50, in methanol (8 ml)
was warmed at reflux for 16 hours. After cooling, the reaction
mixture was concentrated and purified by flash chromatography
(silica gel, 95:5 CH.sub.2 Cl.sub.2 : 10% NH.sub.4 OH/CH.sub.3 OH)
to give 23 mg (0.080 mmol) of product as an oil.
The above product (18 mg, 0.063 mmol) was dissolved in CH.sub.2
Cl.sub.2 (1 mL) and pyridine (0.05 mL). The resulting solution was
cooled to 0.degree. C. and treated with
4-(3-hexyl-2-imidazolidinon-1-yl)benzenesulfonyl chloride (22 mg,
0.063 mmol). The mixture was allowed to stir at 0.degree. C. for
hours and was then purified by flash chromatography (silica gel,
95:5 CH.sub.2 Cl.sub.2 :10% NH.sub.4 OH/CH.sub.3 OH) to give the
desired product (21 mg, 0.035 mmol) as an oil: 1HNMR (CD3OD)
.delta.8.53 (s, 1H), 8.44 (d, 1H, J=5.0), 7.83 (d, 1H, J=7.9), 7.63
(m, 4H), 7.40 (dd, 1H, J=5.0, 7.9), 6.98 (m, 4H), 4.72 (dd, 1H,
J=4.0, 8.4), 3.80 (m, 2H), 3.49 (m, 2H), 3.22 (t, H, J=7.2), 2.78
(m, 2H), 2.62 (m, 2H), 1.55 (m, 2H), 1.31 (m, 6H), 1.01 (s, 3H),
0.99 (s, 3H), 0.89 (m, 3H).
Following the procedure outlined above, the compounds in Table 4
were prepared.
TABLE 4 ______________________________________ ##STR53## Ex- am-
ple R Selected .sup.1 H NMR (CD.sub.3 OD) Data
______________________________________ 94 4-iodophenyl 7.82(d, 2H,
J=8.6), 7.42(d, 2H, J=8.6) 95 4-[[(hexylamino)car- 7.55(d, 2H,
J=8.8), 7.42(d, 2H, bonyl]amino]phenyl J=8.8), 3.11(t, 2H, J=7.0),
1.49(m, 2H), 1.30(m, 6H), .089(m, 3H)
______________________________________
EXAMPLE 96 ##STR54##
(R)-4-amino-.alpha.-(bromomethyl)-3,5-dichlorobenzenemethanol,
dimethyl-1,1-dimethylethylsilyl ether
A solution of t-butyldimethylsilyl chloride (1.67 g, 11.1 mmol) in
DMF (15 mL) was added slowly to a stirred solution of
(R)-4-amino-.alpha.-(bromomethyl)-3,5-dichlorobenzenemethanol (2.1
g, 7.4 mmol, see Judkins, et. al, European Patent Application 0 460
924) and imidazole (0.75 g, 11.1 mmol) in DMF (6 mL) with an
ice-water bath cooling. After being stirred at RT for 3h, the
reaction mixture was poured into water (300 mL) and the product was
extracted with ether. The organic phase was washed with saturated
aqueous sodium bicarbonate solution, brine, dried(MgSO.sub.4) and
evaporated to dryness. The crude product was purified on silica
(95/5 hexane/ethyl acetate) to give the title compound (2.73 g, 93%
.sup.1 H NMR (400 MHz, CDCl.sub.3) .delta.7.14 (s, 2H), 4.67 (dd,
1H, J=2.1, 6.4 Hz), 3.33 (m, 2H), 0.87 (s, 9H), 0.89(s, 6H)
EXAMPLE 97 ##STR55## (R)-N-[2-[4-(Aminophenyl)]ethyl]-2-[(dimethyl-
1,1-dimethylethyl-silyl)oxy]-2-(4-amino-3,5-dichlorophenyl)ethylamine
O-TBDMS bromo compound from Example 96 (2.73 g, 6.86 mmol) was
dissolved in CH.sub.3 CN (50 mL) and 4-amino-phenethylamine (1.86
g, 13.72 mmol) was added, followed by the addition of
N,N'-diisopropylethylamine (3.58 mL, 20.6 mmol) and sodium iodide
(1.03 g, 6.86 mmol). After being heated at reflux for 48 h, the
reaction mixture was concentrated and the residue chromatographed
on silica (50/50 ethyl acetate/hexane) to provide the title
compound (2.3 g, 75 %): 1H NMR (400 MHz, CDCl.sub.3) .delta.7.08
(s, 2H), 6.94 (AA', 2H, J=8.4 Hz), 6.60 (BB', 2H, J=8.4 Hz), 4.63
(m, 1H), 4.37 (s, 2H), 3.53 (br s, 2H), 2.87-2.60 (m, 6H), 0.80 (s,
9H),-0.03 (s, 6H)
EXAMPLE 98 ##STR56##
(R)-N-[2-[4-(Aminophenyl)]ethyl]-2-hydroxy-2-(4-amino-3,5-dichlorophenyl)e
t hylamine
To a stirred solution of silyl compound from Example 97 (2.2 g, 4.8
mmol) in THF (20 mL) at RT was added tetrabutylammonium fluoride
(10 mL of 1.0 M solution in THF) in one portion. After being
stirred at RT for 2h, the reaction mixture was concentrated and
chromatographed on silica (10/90 CH.sub.3 OH/CH.sub.2 Cl.sub.2) to
give the title compound (1.59 g, 97 %): .sup.1 H NMR (400 MHz,
CD.sub.3 OD) .delta.7.15 (s, 2H), 6.92 (AA', 2H, J=8.3 Hz), 6.60
(BB', 2H, 8.3 Hz), 4.58 (m, lH), 2.83-2.65 (m, 6H)
EXAMPLE 99 ##STR57##
(R)-N-[4-[2-[[2-Hydroxy-2-(4-amino-3,5-dichlorophenyl)ethyl]amino]-ethyl]-
p henyl]-4-(hexylaminocarbonylamino)benzenesulfonamide
Following the procedure outlined in Example 18 and 25, the title
compound was prepared from the aniline derivative from Example 98:
NMR (400 MHz, CD.sub.3 OD) 7.57 (AA', 2H, J=2.7 Hz), 7.42 (BB', 2H,
J=2.7 Hz), 7.16 (s, 2H), 7.04 (AA', 2H, J=2.0 Hz), 7.00 (BB', 2H,
J=2.0 Hz), 4.58 (t, 1H, j=7.1 Hz), 3.14 (t, 1H, J=7.0 Hz), 2.80 (m,
2H), 2.73 (m, 4H), 1.49 (m, 2H), 1.32 (m, 6H), 0.90 (t, 3H, J=6.7
Hz). ESI MS m/z 622 (M).
Following the procedure outlined in Examples 96-99, the compounds
in Table 5 were prepared.
TABLE 5 ______________________________________ ##STR58## Ex- am-
Selected ple R .sup.1 H NMR (CD.sub.3 OD) Data
______________________________________ 100 1- 7.82(d, 1H, J=9.2Hz),
7.47(m, [(octylamino)carbonyl]- 2H), 3.93(t, 2H, J=9.0Hz), 3.18
indolin-5-yl (m, 4H), 1.53(m, 2H), 1.31(m, 10H), 0.88(t, 3H,
J=7.1Hz) 101 4-(3-hexyl-2- 7.68-7.60(AA'BB', 4H), 3.82(t,
imidazolidinon-1- 2H, J=6.2Hz), 3.52(t, 2H, yl)phenyl J=6.2Hz),
3.30(t, 2H, J=6.0Hz), 1.54(m, 2H), 1.31(m, 6H), 0.89(t, 3H J=6.0Hz)
102 4-(3-octyl-2- 7.65-7.60(AA'BB', 4H), 3.82(t, imidazolidinon-1-
2H, J=6.2Hz), 3.52(t, 2H, yl)phenyl J=6.2Hz), 3.29(t, 2H, J=6.0Hz),
1.54(m, 2H), 1.30(m, 10H), 0.87(t, 3H, J=6.1HZ)
______________________________________
EXAMPLE 103 ##STR59##
(R)-N-[4-[2-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-benze
n esulfonamide
A solution of 5 g of 4-aminophenethyl alcohol in 50 mL of DMF was
silylated with 5.5 g of t-butyldimethylsilyl chloride (TBDMS-Cl)
and 2.5 g of imidazole overnight at room temperature. Extraction of
the product following an aqueous ammonium chloride workup afforded
6.6 g of the O-TBDMS ether. This aniline derivative was then
coupled to benzenesulfonyl chloride in pyridineodichloromethane to
give the sulfonamide in greater than 80% yield after
chromatographic purification. The TBDMS group of the sulfonamide
was removed with methanolic HC1 at room temperature for 30 min. The
crude alcohol was oxidized to the corresponding carboxylic acid
with Jones reagent in acetone (RT 30 min, ethyl acetate
extraction).
To a solution of 180 mg of (R)-octopamine and 300 mg of the
resultant 4-N-benzenesulfonamidophenylacetic acid in 7 mL of DMF
was added 0.5 mL of triethylamine and 490 mg of
benzotriazolyl-N-oxy-tris(dimethylamino)phosphonium
hexafluorophosphate. The reaction mixture was stirred at RT 2h,
flash chromatography over silica gel eluting with 95:5
chloroform-methanol gave 322 mg of purified amide.
A solution of 220 mg of this amide in 13 mL of 1.0 M borane-THF was
refluxed under argon for 2h followed by the addition of 3 mL of
N,N-dimethylaminoethanol and further reflux for another hour. The
solvent and excess volatiles were removed in vacuo and the residual
solid was taken up in acetone and purified by PLC on silica gel
(9:1 ethyl acetate:methanol) to yield 61 mg of the title compound:
.sup.1 H NMR (500 MHz, CD.sub.3 OD) .delta.7.73 (dt, 2H, J=2.1,
8.2Hz), 7.53 (tt, 1H, J=l.4, 7.6Hz), 7.44 (t, 2H, J=8 Hz), 7.18 (d,
2H, J=8.4 Hz), 7.05 (ABq, 4H, Jab=8.5 Hz), 6.76 (d, 2H, J=8.4Hz),
4.75 (dd, 1H, J=7.5, 7.6 Hz), 3.05-2.90 (m, 4H), 2.81 (t, 2H, J=7.6
Hz). Mass spec calcd. 412.5 found 4 13.2.
EXAMPLE 104 ##STR60##
(R)-N-[4-[2-[[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino]ethyl]phenyl]-4-iod
o benzenesulfonamide
Following the procedure outlined in Example 103, the title compound
was prepared: .sup.1 H NMR (500 MHz, CD.sub.3 OD) .delta.7.77 (d,
2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 7.15 (d, 2H, J=8.5 Hz), 7.02
(ABq, 4H, Jab=8.7 Hz), 6.75 (d, 2H, J=8.5 Hz), 4.67 (dd, 1H, J=4.4,
6.6 Hz), 2.90-2.66 (m, 6H). Mass spec calcd. 538.4 found 538.9.
EXAMPLE 105 ##STR61## 3-(2-bromoacetyl)benzonitrile
To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in mL
of ethyl ether was added 1.02 g (3.52 mmol, 0.5 equiv) of
dibromobarbituric acid. The mixture was allowed to stir at room
temperature overnight. The resultant white slurry was filtered and
the tiltrate was concentrated. Purification by flash chromotography
(silica gel, ethyl acetate/hexane) gave 1.28 g (81%) of the title
compound as a white solid: 1H NMR (400 MHz, CDCl.sub.3) .delta.
8.26 (t, 1H, J=1.4 Hz), 8.20 (td, 1H, J=1.5, 8.0 Hz), 7.87 (dd, 1H,
J=1.3, 7.8 Hz), 7.64 (t, 1H, J=7.9 Hz), 4.40 (s, 2H).
EXAMPLE 106 ##STR62##
(R)-.alpha.-Bromomethyl-3-cyanophenylmethanol
To a suspension of 181 mg (0,623 mmol) of
(R)-tetrahydro-1-methyl-3,3-diphenyl-
1H,3H-pyrrolo[1,2c][1,3,21oxazaborole-borane (R-OAB catalyst) in 6
mL of THF at 0.degree. C. was added dropwise 6.24 mL (6.24 mmol) of
a 1 M solution of borane in THF. The resultant clear solution was
allowed to stir for 5 min, and then a solution of 1.27 g (5.67
mmol) of bromoketone from Example 105 in 6 mL of THF was added
slowly over 1 h. After the reaction was allowed to stir for 30 rain
more, it was quenched by the dropwise addition of 6 mL of methanol
and concentrated. Purification by flash chromatography (silica gel,
20-25% ethyl acetate/hexane) provided 944 mg (74%) of the title
compound as a clear oil which crystallized: .sup.1 H NMR (400 MHz,
CDCl.sub.3) 8 7.70 (d, 1H, J=1.5 Hz), 7.62-7.60 (m, 2H), 7.48 (t,
1H, J=7.7 Hz), 4.95 (rid, 1H, J=3.4, 8.4 Hz), 3.63 (dd, 1H, J=3.4
Hz), 3.49 (dd, 1H, J=8.4 Hz).
EXAMPLE 107 ##STR63## (R)-(3-cyanophenyl)oxirane
To a solution of 937 mg (4.14 mmol) of bromohydrin from Example 106
in 8 mL of methanol was added 601 mg (4.35 mmol, 1.05 equiv) of
potassium carbonate. The reaction mixture was allowed to stir at
room temperature for 7 h. It was then diluted with ethyl acetate,
washed with water, dried over magnesium sulfate, and concentrated.
Purification by flash chromatography (silica gel, 20% ethyl
acetate/hexane) provided 573 mg (95%) of the title compound: .sup.1
H NMR (400 MHz, CDCl.sub.3) .delta.0.7.59-7.55 (m, 2H), 7.49 (dd,
1H, J=1.6, 7.9 Hz), 7.44 (t, 1H, J=7.7 Hz), 3.87 (dd, 1H, J=2.5,
4.0 Hz), 3.17 (dd, 1H, J=4.1, 5.5 Hz), 2.74 (dd, 1H, J=2.5, 5.4
Hz).
EXAMPLE 108 ##STR64##
(R)-N-[2-[4-(aminophenyl)]ethyl]-2-hydroxy-2-(3-cyanophenyl)ethyl-carbamic
acid 1,1-dimethylethyl ester
Following the procedures outlined in Examples 17 and 18, the title
compound was prepared from the epoxide from Example 107: .sup.1 H
NMR (400 MHz, CDCl.sub.3) .delta.7.58-7.52 (br m, 3H), 7.41 (t, 1H,
J=7.5 Hz), 6.89 (br d, 2H, J=7.6 Hz), 6.65 (br d, 2H, J=7.8 Hz),
4.82 (br dd, 1H, J=2.7, 7.9 Hz), 3.42-3.05 (br m, 4H), 2.75-2.55
(br m, 2H).
EXAMPLE 109 ##STR65##
(R)-N-[4-[2-[[2-Hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-4-(hexy
l aminocarbonylamino)benzenesulfonamide
Following the procedure outlined in Example 25, the title compound
was prepared from the Boc aniline derivative from Example 108:
.sup.1 H NMR (400 MHz, CD.sub.3 OD) .delta.7.70 (s, 1H), 7.63-7.57
(m, 4H), 7.48 (t, 1H, J=7.7 Hz), 7.43 (d, 2H, J=8.9 Hz), 7.06 (d,
2H, J=8.5 Hz), 6.99 (d, 2H, J=8.5 Hz), 4.77 (dd, 1H, J=3.9, 8.5
Hz), 3.15 (t, 2H, J=7.0 Hz), 2.86-2.69 (m, 6H), 1.49 (br m, 2H),
1.31 (br m, 6H), 0.90 (br t, 3H).
EXAMPLE 110 ##STR66##
(R)-N-[4-[2-[[2-Hydroxy-2-(3-cyanophenyl)ethyl]amino]ethyl]phenyl]-3-quino
l inesulfonamide
Following the procedure outlined in Example 25, the title compound
was prepared from the Boc aniline derivative from Example and
3-quinolinesulfonyl chloride: .sup.1 H NMR (400 MHz, CD.sub.3 OD)
.delta.9.02 (d, 1H, J=2.3 Hz), 8.68 (d, 1H, J=1.9 Hz), 8.06 (d, 1H,
J=8.3 Hz), 8.02 (d, 1H, J=7.9 Hz), 7.90 (ddd, 1H, J=1.4, 7.0, 8.4
Hz), 7.72-7.69 (m, H), 7.62-7.58 (m, 2H), 7.47 (t, 1H, J=7.7 Hz),
7.07 (d, 2H, J=8.7 Hz), 7.03 (d, 2H, J=8.7 Hz), 4.76 (dd, 1H,
J=4.0, 8.5 Hz), 2.85-2.68 (m, 6H).
Following the procedures outlined for Examples 14-31, the compounds
listed in Table 6 were prepared.
TABLE 6 ______________________________________ ##STR67## Ex- am-
ple R Selected .sup.1 H NMR (CD.sub.3 OD)
______________________________________ Data 111 4-(3-hexyl-2,4-
4.40(s, 2H), 3.54(m, 2H), 1.68- imidazolidinedion-1- 1.59(m, 2H),
1.37-1.28(m, 6H), yl)phenyl 0.91(m, 3H). 112 4-(3-octyl-2,4-
4.40(s, 2H), 3.52(m, 2H), 1.68- imidazolidinedion-1- 1.59(m, 2H),
1.38-1.23(m, 10H), yl)phenyl 0.89(m, 3H). 113 4-[2-(4- 7.66(s, 1H),
5.35(m, 1H), 3.22- cyclohexylbutyl)- 3.32(m, 5H), 2.95(m, 2H),
2.90(t, oxazol-5-yl]phenyl, J=6.5Hz, 2H), 1.8(m, 2H),
trihydrochloride 1.69(m, 5H), 1.45(m, 2H), 1.24(m, 6H), 0.89(m. 2H)
114 4-[2-[2-(4- 7.49(s, 1H), 7.2(m, 2H), 6.99(m,
fluorophenyl)ethyl]- 2H), 4.90(m, 1H), 3.05(m, 4H),
oxazol-5-yl]phenyl 2.70-2.85(m, 6H) 115 4-[2-(3- 7.51(s, 1H),
4.90(m, 1H), 2.65- cyclopentylpropyl)- 2.90(m, 8H), 1.80(m, 5H),
1.46- oxazol-5-yl]phenyl 1.62(m, 4H), 1.05(m, 2H) 116
4-(4-hexyl-3-oxo- 8.04(s, 1H), 3.69(m, 2H), 1.78-
[1,2,4]-triazol-2- 1.69(m, 2H), 1.39-1.28(m, 6H), yl)phenyl 0.90(m,
3H). 117 4-(4-octyl-3-oxo- 8.03(s, 1H), 3.69(m, 2H), 1.77-
[1,2,4]-triazol-2- 1.69(m, 2H), 1.38-1.25(m, 10H), yl)phenyl
0.89(m, 3H). 118 4-(4-heptyl-5-methyl- 2.28(s, 3H), 1.67(t, 2H,
J=6.9Hz), [1,2,3]-triazol-2- 1.36-1.34(m, 4H), 1.31-1.29(m,
yl)phenyl 2H), 1.18(d, 4H, J=2.5Hz), 0.88(t, 3H, J=7.0Hz) 119 4-[2-
7.50(s, 1H), 4.83(m, 1H), 2.95- (cyclopentylmethyl)- 2.70(m, 8H),
2.33(m, 1H), 1.81 oxazol-5-yl]phenyl (m, 2H), 1.67(m, 2H), 1.57(m
2H), 1.27(m, 2H) 120 4-(4- 7.36-7.33(m, 5H), 7.27(t, 4H,
diphenylhydroxy- J=5.3Hz), 7.23(d, 2H, J=4.5Hz), methyl-5-methyl-
2.04(s, 3H) [1,2,3]-triazol-2- yl)phenyl 121 4-[4-[bis(4-
7.36-7.33(m, 5H), 7.05-6.99(m, fluorophenyl)hydroxy- 8H), 2.09(s,
3H) methyl]-5-methyl- [1,2,3]-triazol-2- yl]phenyl 122
4-(3-hexylpyrazol-1- 8.13(d, 1H, J=2.5Hz), 7.75(s, yl)phenyl 4H),
6.33(d, 1H, J=2.5Hz), 2.60 (t, 2H, J=7.6Hz), 1.65(m, 2H),
1.38-1.28(m, 6H), 0.88(t, 3H, J= 6.8Hz) 123 4-[5-(1- (CDCl.sub.3)
4.98-4.91(m, 2H), 3.23- hydroxypentyl)-[1,2,4]- 3.19(m, 1H),
1.99-1.93(m, 2H), oxadiazol-3-yl]phenyl 1.49-1.32(m, 4H),
0.92-0.86(m, 3H) 124 4-[4-[(4-fluorophenyl)- 7.44-7.42(m, 2H),
7.09-7.02(m, hydroxymethyl]-5- 6H), 2.20(s, 3H)
methyl-[1,2,3]-triazol- 2-yl]phenyl
______________________________________
* * * * *